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KLK9 (kallikrein-related peptidase 9)

Written2016-09Panagiotis G. Adamopoulos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens. 157 01, Panepistimiopolis, Athens, Greece / ascorilas@biol.uoa.gr

Abstract Kallikreins (KLKs) represent the largest cluster of serine peptidases, which is composed of 15 members (KLK1-15). The human kallikrein-related peptidase 9 gene (KLK9), like the rest of the KLK genes, encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins). The human KLK9 gene is located at 19q13.41 and consists of 5 exons and 4 intervening introns. Although KLK9 expression has been detected in various normal human tissues, differences in mRNA and protein expression levels have been observed. Like other KLKs, KLK9 is found differentially expressed in multiple human malignancies. Clinical studies regarding the KLK9 expression analysis in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses significant prognostic ability and therefore could be a strong, independent marker of favorable prognosis in patients with breast cancer. In addition, the prognostic potential of the KLK9 mRNA expression levels in ovarian cancer has been clarified, since patients with KLK9-positive tumors demonstrate significantly longer progression-free and overall survival in comparison with KLK9-negative patients. Finally, KLK9 could serve as a prognostic biomarker for patients diagnosed with high-grade astrocytoma, as its expression level is associated with decreased survival of patients. Although the precise localization and structure of the KLK9 gene has now been fully characterized, its functional roles and connections to human diseases are still incompletely understood and merit further investigation.

Keywords Kallikreins; KLK9; KLK-L3; KLKL3; biomarker; proteolytic cascades; breast cancer; ovarian cancer; astrocytoma

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Identity

Alias_nameskallikrein 9
Alias_symbol (synonym)KLK-L3
Other aliasKLKL3
HGNC (Hugo) KLK9
LocusID (NCBI) 284366
Atlas_Id 47324
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 51002513 and ends at 51009634 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK9.png]
Local_order Telomere to centromere.
Note The name of this gene is "kallikrein-related peptidase 9", while the name of its product is "kallikrein-9 precursor".

DNA/RNA

 
  Detailed structure of the annotated full-length mRNA transcript (NM_005551.4) of the KLK9 gene. The full-length KLK9 mRNA transcript is composed of 5 exons. Exons are depicted as boxes and introns as lines; gray and white boxes represent coding and non-coding exons, respectively. Numbers inside boxes and above lines indicate the length of each exon or intron in nucleotides. Finally, the translation start and stop codons are also shown.
Description The KLK9 gene consists of 5 exons and 4 intervening introns, spanning a region of 7081 bp genomic DNA.
Transcription A single mRNA transcript (NM_005551.4) of the KLK9 gene, with a total length of 1438 nucleotides, has been annotated. Expression of the KLK9 gene has been detected in various normal human tissues; still, differences in mRNA and protein expression levels have been observed. In particular, the highest mRNA levels of the KLK9 gene have been detected in stomach and vagina. In addition, KLK9 is expressed in high levels in the brain, cervix, esophagus, and fallopian tube, while normal expression levels are observed in breast, prostate, testis, thymus, thyroid, liver, lung, small intestine, spinal cord, and trachea (Shaw and Diamandis, 2007).
However, recent evidence derived from next-generation sequencing approaches has confirmed the existence of 10 novel alternative KLK9 transcripts (KLK9 v.2 -> v.11) that have already been submitted in GenBank® database (GenBank® accession numbers: KX571238 - KX571247 accordingly).
Pseudogene Not yet identified.

Protein

Description The protein encoded by the KLK9 gene is a kallikrein-related serine protease of 250 amino acid residues, with a calculated molecular mass of 25.6 kDa. Similar to other tissue kallikreins, the KLK9 protein is produced as a pre-proenzyme consisting of 250 amino acids, which is processed into a mature form with enzymatic activity (229 amino acids). In addition, KLK9 protein harbors a signal peptide of 19 amino acid residues and a 3-aa pro-segment (Yousef and Diamandis, 2000).
Localisation KLK9 is mainly localized in the cytoplasm.
Function Like the rest of the KLK genes, the KLK9 gene encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins) (Schachter, 1980).
Homology Homology tests have demonstrated that human KLK9 protein shares the highest homology with human KLK11 (40%). In addition, KLK9 protein sequence is 38% homologous with the sequence of KLK5 and 33% homologous with the one of tissue kallikrein ( KLK1) (Yousef and Diamandis, 2000).

Mutations

Note No germinal or somatic mutations have been associated with cancer.

Implicated in

Note No cytogenetic abnormalities have been identified so far.
  
Entity Breast cancer
Prognosis Clinical studies regarding the expression analysis of the KLK9 gene in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses strong prognostic ability. In particular, breast cancer patients with KLK9-positive tumors exhibit significantly longer disease-free survival (DFS) as well as overall survival (OS) compared to those who are KLK9-negative. As a result, mRNA overexpression of the KLK9 gene in breast tumors is found to be associated with increased DFS and OS leading to the conclusion that KLK9 mRNA levels could be a strong, independent marker of favorable prognosis in breast cancer (Yousef et al., 2003).
  
  
Entity Ovarian cancer
Prognosis Similar studies regarding the KLK9 mRNA expression analysis in ovarian tumor samples have clarified the prognostic potential of the KLK9 gene in ovarian cancer. KLK9 mRNA overexpression can serve as an independent favorable prognostic marker for ovarian cancer patients, since patients with KLK9-positive tumors demonstrated significantly longer progression-free and overall survival in comparison with KLK9-negative patients (Yousef et al., 2001).
  
  
Entity Astrocytoma
Prognosis KLK9 protein expression analysis in two distinct tissue microarrays containing grade III and IV astrocytoma samples revealed that increased KLK9 expression is associated with decreased survival of patients, thus suggesting its utility as a prognostic biomarker for patients diagnosed with high-grade astrocytoma (Drucker et al., 2015).
  

Bibliography

The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer
George M. Yousef, Andreas Scorilas, Terukazu Nakamura, Mohamed Abd Ellatif,
Breast Cancer Res Treat. 2003 Mar;78(2):149-58.
PMID 12725415
 
Distribution of 15 Human Kallikreins in Tissues and Biological Fluids
Julie L.V. Shaw and Eleftherios P. Diamandis
Clin Chem. 2007 Aug;53(8):1423-32.
PMID 17573418
 
Prognostic significance of multiple kallikreins in high-grade astrocytoma
Kristen L. Drucker, Caterina Gianinni, Paul A. Decker, Eleftherios P. Diamandis and Isobel A. Scarisbrick
BMC Cancer. 2015 Aug 1;15:565.
PMID 26231762
 
Kallikreins (kininogenases)A group of serine proteases with bioregulatory actions
Schachter, M.
Pharmacol Rev. 1979 Mar;31(1):1-17
PMID 94166
 

Citation

This paper should be referenced as such :
Adamopoulos PG, Scorilas A
KLK9 (kallikrein-related peptidase 9);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/KLK9ID47324ch19q13.html


External links

Nomenclature
HGNC (Hugo)KLK9   6370
Cards
AtlasKLK9ID47324ch19q13
Entrez_Gene (NCBI)KLK9  284366  kallikrein related peptidase 9
AliasesKLK-L3; KLKL3
GeneCards (Weizmann)KLK9
Ensembl hg19 (Hinxton)ENSG00000213022 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000213022 [Gene_View]  chr19:51002513-51009634 [Contig_View]  KLK9 [Vega]
ICGC DataPortalENSG00000213022
TCGA cBioPortalKLK9
AceView (NCBI)KLK9
Genatlas (Paris)KLK9
WikiGenes284366
SOURCE (Princeton)KLK9
Genetics Home Reference (NIH)KLK9
Genomic and cartography
GoldenPath hg38 (UCSC)KLK9  -     chr19:51002513-51009634 -  19q13.41   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLK9  -     19q13.41   [Description]    (hg19-Feb_2009)
EnsemblKLK9 - 19q13.41 [CytoView hg19]  KLK9 - 19q13.41 [CytoView hg38]
Mapping of homologs : NCBIKLK9 [Mapview hg19]  KLK9 [Mapview hg38]
OMIM605504   
Gene and transcription
Genbank (Entrez)AY551001 BC140229 BC141613 BC172590
RefSeq transcript (Entrez)NM_012315
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KLK9
Cluster EST : UnigeneHs.448942 [ NCBI ]
CGAP (NCI)Hs.448942
Alternative Splicing GalleryENSG00000213022
Gene ExpressionKLK9 [ NCBI-GEO ]   KLK9 [ EBI - ARRAY_EXPRESS ]   KLK9 [ SEEK ]   KLK9 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK9 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)284366
GTEX Portal (Tissue expression)KLK9
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UKQ9   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UKQ9  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UKQ9
Splice isoforms : SwissVarQ9UKQ9
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
PhosPhoSitePlusQ9UKQ9
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)KLK9
DMDM Disease mutations284366
Blocks (Seattle)KLK9
SuperfamilyQ9UKQ9
Human Protein AtlasENSG00000213022
Peptide AtlasQ9UKQ9
HPRD05692
IPIIPI00007713   IPI00423197   
Protein Interaction databases
DIP (DOE-UCLA)Q9UKQ9
IntAct (EBI)Q9UKQ9
FunCoupENSG00000213022
BioGRIDKLK9
STRING (EMBL)KLK9
ZODIACKLK9
Ontologies - Pathways
QuickGOQ9UKQ9
Ontology : AmiGOserine-type endopeptidase activity  extracellular region  proteolysis  
Ontology : EGO-EBIserine-type endopeptidase activity  extracellular region  proteolysis  
NDEx NetworkKLK9
Atlas of Cancer Signalling NetworkKLK9
Wikipedia pathwaysKLK9
Orthology - Evolution
OrthoDB284366
GeneTree (enSembl)ENSG00000213022
Phylogenetic Trees/Animal Genes : TreeFamKLK9
HOVERGENQ9UKQ9
HOGENOMQ9UKQ9
Homologs : HomoloGeneKLK9
Homology/Alignments : Family Browser (UCSC)KLK9
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK9 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK9
dbVarKLK9
ClinVarKLK9
1000_GenomesKLK9 
Exome Variant ServerKLK9
ExAC (Exome Aggregation Consortium)KLK9 (select the gene name)
Genetic variants : HAPMAP284366
Genomic Variants (DGV)KLK9 [DGVbeta]
DECIPHERKLK9 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLK9 
Mutations
ICGC Data PortalKLK9 
TCGA Data PortalKLK9 
Broad Tumor PortalKLK9
OASIS PortalKLK9 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK9  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKLK9
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLK9
DgiDB (Drug Gene Interaction Database)KLK9
DoCM (Curated mutations)KLK9 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK9 (select a term)
intoGenKLK9
NCG5 (London)KLK9
Cancer3DKLK9(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605504   
Orphanet
MedgenKLK9
Genetic Testing Registry KLK9
NextProtQ9UKQ9 [Medical]
TSGene284366
GENETestsKLK9
Target ValidationKLK9
Huge Navigator KLK9 [HugePedia]
snp3D : Map Gene to Disease284366
BioCentury BCIQKLK9
ClinGenKLK9
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD284366
Chemical/Pharm GKB GenePA30159
Clinical trialKLK9
Miscellaneous
canSAR (ICR)KLK9 (select the gene name)
Probes
Litterature
PubMed13 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLK9
EVEXKLK9
GoPubMedKLK9
iHOPKLK9
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Mon May 22 09:14:45 CEST 2017

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