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KLK4 (kallikrein-related peptidase 4)

Written2009-01John Lai, Ying Dong, Judith A Clements
Hormone Dependent Cancer Program, Institute of Health, Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPRSS17
kallikrein 4 (prostase
Alias_symbol (synonym)EMSP
EMSP1
PSTS
KLK-L1
Other aliasARM1
MGC116827
MGC116828
Prostase
HGNC (Hugo) KLK4
LocusID (NCBI) 9622
Atlas_Id 41084
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 50906352 and ends at 50910738 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK4.png]
Local_order Telomere to centromere.
Fusion genes
(updated 2016)		KAT6A (8p11.21) / KLK4 (19q13.41)KIF1C (17p13.2) / KLK4 (19q13.41)KLK4 (19q13.41) / KLKP1 (19q13.33)

DNA/RNA

 
  Genomic and protein structure of the KLK4 gene. The KLK4 gene is classically comprised of 5 exons (grey boxes, classic numerals) and 4 introns (roman numerals), although extra 5' UTR sequences in exon 1a have also been described. Shown here are the three putative alternative transcription start sites (TSS1, TSS2 and TSS3). Also shown are the postions of ATG1 and ATG2 that would be utilised from these variant transcripts. The amino acid numbering for the residues of the catalytic triad (His71, Asp116, Ser207) are relative to the full-length protein starting from ATG1.
Description The gene encompasses 4.38 kb of gDNA.
Transcription Three alternative transcription start sites (TSSs) have been predicted or identified experimentally for the KLK4 gene. TSS1 was identified using 5' RACE and is located 639 bp upstream of TSS2, which was predicted using in silico analysis. TSS3 was also identified using 5' RACE and is located 1396 bp downstream of TSS1.
Nine KLK4 variant transcripts have been identified. These variants include the TSS variants, variants with 5' UTR deletion for TSS1 and TSS2 transcripts, exon 4 deletion and partial intron II (12bp) insertion variants, intron 3 insertion variants, and variants with combinations thereof.
Pseudogene Not identified.

Protein

Description Two KLK4 protein isoforms, full-length KLK4 (254 amino acids) and an N-terminal truncated KLK4 (205 amino acids) have been described. Full-length KLK4 has a secretion signal (pre-) peptide (26 amino acids), followed by an activation (pro-) peptide (4 amino acids) and the mature chain (224 amino acids) with 1 potential N-linked glycosylation site. The catalytic triad of His71, Asp116, Ser207 (relative to Met = 1 and encoded by ATG1 in exon 1) is conserved and is essential for proteolytic activity. After synthesis as a KLK4 full-length protein, the signal peptide is then cleaved and pro-KLK4 (zymogen) is subsequently secreted from the cell. Upon activation, the propeptide is removed to generate the mature active enzyme. KLK4 complexes with alpha(1)-antitrypsin and alpha(2)-antiplasmin and alpha(2)-macroglobulin.
The N-terminal truncated KLK4 isoform initiated from the ATG2 in exon 2, has the pre-pro-region and 9 amino acids from the mature KLK4 omitted, although the catalytic triad remains. Further, the truncated KLK4 isoform is not glycosylated despite retaining the potential N-linked glycosylation site.
Expression The KLK4 gene was originally designated the PRSS17 gene and was cloned from the cells of the enamel organ epithelia of developing teeth in pig using degenerate primers encoding the EMPS1 protein. Subsequent studies in human tissues using Northern blot analysis have shown that KLK4 mRNA expression is predominantly localised to the prostate, although more sensitive RT-PCR experiments have shown that the breast, ovary, endometrium, salivary gland, lung, adrenal gland, colon, trachea, brain, testis, spinal cord, thyroid, skin and kidney also express KLK4 mRNA at low to modest levels. KLK4 mRNA has also been detected in sebaceous glands, sweat glands, hair follicles, stratum basale, stratum spinosum and stratum granulosum by in situ hybridisation experiments. In pig, KLK4 mRNA is expressed in the endometrium in the early stages of the oestrous cycle.
KLK4 protein has been detected in a wide range of tissues at low (adrenal, aorta, brain, breast, cervix, heart, kidney, liver, muscle, pancreas, pituitary, salivary gland, small intestine, spinal cord, spleen, testis, skin, thyroid, and uterus) to high (prostate) levels. Modest levels of KLK4 protein have also been detected in body fluid, such as seminal plasma and urine. High KLK4 levels have also been detected in the prostate, breast and ovarian cancer tissues from patients.
Localisation Full-length KLK4 encodes a secreted protein and is localised intracellularly to the cytoplasm, although GFP labelled N-terminal truncated isoforms have been found to be predominantly localised to the nucleus.
Function To date, the major biological function of KLK4 has been derived from porcine studies which have shown that KLK4 is important in dental enamel mineralisation by degrading amelogenin, the major protein in the enamel matrix of developing teeth. More recently, KLK4 was also reported to degrade porcine enamelin which is another protein found in developing teeth. Further, in mice, KLK4 was only expressed by transition and maturation stage ameloblasts, which is consistent with KLK4 functioning primarily to degrade the enamel matrix in developing teeth.
The role of KLK4 in the prostate, a tissue that highly expresses KLK4, is less clearly defined although it is thought to be important in prostate cancer progression given its role in degrading extracellular matrix (ECM) proteins in teeth, and potentially increasing IGF levels by degrading IGFBP3, IGFBP4, IGFBP5, IGFBP6. KLK4 is also reported to activate pro- HGFA and thereby potentially leading to tumour progression through activation of the MET receptor. A substrate specificity screening study has shown that full-length KLK4 has trypsin-like specificity and potentially activates proteins, such as, prostate specific antigen (PSA) / KLK3, bone morphogenetic protein (BMP) family and parathyroid hormone-related protein ( PTHrP ) that are involved in normal and neoplastic prostate (patho)-physiology. Recombinant KLK4 was also reported to be a better activator of PSA and single chain urokinase-type plasminogen activator than KLK2. More recently, KLK4 was shown to activate other members of the kallikrein-related peptidase family including KLK1, KLK2, KLK3, KLK5, KLK6, KLK9, KLK11, KLK12, KLK13, KLK14, KLK15. However, the precise physiological role for KLK4 in the prostate and other tissues remains to be identified. The function of the N-terminal truncated KLK4 remains to be established.
Homology At the protein level, KLK4 shares 25%, (KLK12), 29% (KLK10), 31% (KLK9), 34% (KLK1, 2, 3), 35% (KLK8, 13), 36% (KLK6), 37% (KLK15), 40% (KLK14), 43% (KLK7), 45% (KLK5) sequence homology with other members of the kallikrein-related peptidase family. Unlike KLK1, KLK2 and KLK3, KLK4 lacks the "kallikrein loop", a region of 11 amino acids encoded in exon 3 and thought to be important in the substrate specificity of these enzymes. KLK4 shares 72% sequence homology to the porcine EMPS1 protein. Bayesian phylogenetic analyses suggests that KLK4, KLK5 and KLK14 may form a sub-family within the kallikrein-related peptidase gene family.

Mutations

Germinal A mutation in the KLK4 gene (G.2142>A) that encodes for a truncated KLK4 protein that lacks S207, which is necessary for catalytic activity, has been shown to associate with autosomal recessive hypomaturation amelogenesis imperfecta, which is a disorder affecting tooth enamel formation. Comparison of tooth enamel in patients with the G- and A-alleles suggest that wild-type KLK4 (G allele) is important for the final removal of the extracellar enamel matrix proteins for normal enamel maturation.

Implicated in

Note
  
Entity Hormone dependent cancers
Note It has been proposed that like PSA, encoded by the KLK3 gene, the KLK4 gene may play a role in hormone dependent cancers given its (a) higher expression in endocrine cells (b) regulation by hormones such as androgens, oestradiol and progestins (c) dysregulated expression in cancer cells and (d) potential role in extra-cellular matrix degradation and growth factor activation.
  
  
Entity Prostate cancer
Note Hormone dependent cancer
Disease Kallikrein 4 has been reported to be more highly expressed in cancerous than benign prostate tissues at both the mRNA and protein levels. For example, a tissue microarray study carried out on 42 benign and 207 malignant prostate tissues found that KLK4 was more highly expressed in prostate cancer cells when compared to benign cells, although one study using sandwich-type immunoassay on 16 malignant and 18 benign prostate tissues found no difference in KLK4 expression. It has also been shown that KLK4 specific antibodies can be detected in sera from prostate cancer patients. In prostate cancer cells, KLK4 has been shown to be up-regulated by androgens at both the mRNA and protein level. In two expression studies using Northern blot analysis, KLK4 mRNA expression was found to be up-regulated by 18- and 1.7 -fold after treatment of LNCaP cells with R1881 for 24 and 48 hr, respectively. Further, prostate cancer cells (PC-3 and DU145) transfected with KLK4 have also been shown to have increased cellular migration, proliferation and colony formation. Over-expression of KLK4 in prostate cancer cells has also been associated with increased migration of these cells to SaOs2 conditioned media and greater attachment to bone matrix proteins collagens I and IV. The role of KLK4 in prostate biology is thought to be mediated in part through activation of the PAR-1/F2R and PAR-2/F2RL1 signalling pathways, although the precise mechanisms and importance in prostate cancer remain to be identified.
Cytogenetics Comparison of two human prostate cell lines, P69SV40Tag (P69) and its tumorigenic subline, M12, and 11 prostate cancer cases showed LOH in M12 at 19q13.42, which is proximal to the KLK4 locus.
Hybrid/Mutated Gene No KLK4 fusion transcript or protein has been reported thus far.
  
  
Entity Epithelial ovarian carcinoma
Note Hormone dependent cancer
Disease Kallikrein 4 is more highly expressed in serous ovarian carcinomas at both the mRNA and protein levels, and high KLK4 mRNA expression is associated with poorly differentiated and late clinical stage ovarian carcinomas. KLK4 mRNA was also found to be expressed in tumour cells isolated from ascites fluid in 60% (6/10) of ovarian cancer patients. KLK4 protein expression was also found to be more highly expressed in paclitaxel-resistant (79/93; 85%) than paclitaxel-sensitive tumours (20/33; 61%), suggesting that KLK4 may have utility as a predictive marker for chemoresistant ovarian cancers. Co-overexpression of KLK4, 5, 6 and 7 in ovarian cancer cells (OV-MZ-6) led to increased invasion in vitro and simultaneous expression of these KLKs in nude mice resulted in increased tumour burden.
Prognosis KLK4 mRNA expression in tumour tissues indicates shorter overall and progression free survival time for epithelial ovarian carcinoma patients. It is also an independent indicator of poor prognosis in patients with grade 1 and 2 tumours.
  
  
Entity Breast cancer
Note Hormone dependent cancer
Disease Comparison of RNA levels from normal and malignant breast tissue using real time RT-PCR showed that KLK4 expression was up-regulated in cancer cells. Further analysis using laser dissection of these tumours and immuno-histochemistry showed that the observed increase of KLK4 expression was due to increased expression in the surrounding stromal cells.
  
  
Entity Endometrial cancer
Note Hormone dependent cancer
Disease KLK4 protein levels were shown by Western blot analysis to be up-regulated in endometrial KLE cells in response to both oestradiol and progestin. This response was increased when cells were simultaneously treated with oestrogen and progesterone.
  
  
Entity Non-small cell lung cancer (NSCLC)
Disease Using a KLK4 ELISA on 51 patients with NSCLC and 50 normal controls, it was shown that KLK4 may have utility as a lung cancer biomarker when used in conjunction with KLK8, KLK10, KLK11, KLK12, KLK13, and KLK14.
  

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Citation

This paper should be referenced as such :
Lai, J ; Dong, Y ; Clements, JA
KLK4 (kallikrein-related peptidase 4)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):944-949.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KLK4ID41084ch19q13.html

External links

Nomenclature
HGNC (Hugo)KLK4   6365
Cards
AtlasKLK4ID41084ch19q13
Entrez_Gene (NCBI)KLK4  9622  kallikrein related peptidase 4
AliasesAI2A1; ARM1; EMSP; EMSP1; 
KLK-L1; PRSS17; PSTS; kallikrein
GeneCards (Weizmann)KLK4
Ensembl hg19 (Hinxton)ENSG00000167749 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000167749 [Gene_View]  chr19:50906352-50910738 [Contig_View]  KLK4 [Vega]
ICGC DataPortalENSG00000167749
TCGA cBioPortalKLK4
AceView (NCBI)KLK4
Genatlas (Paris)KLK4
WikiGenes9622
SOURCE (Princeton)KLK4
Genetics Home Reference (NIH)KLK4
Genomic and cartography
GoldenPath hg38 (UCSC)KLK4  -     chr19:50906352-50910738 -  19q13.41   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLK4  -     19q13.41   [Description]    (hg19-Feb_2009)
EnsemblKLK4 - 19q13.41 [CytoView hg19]  KLK4 - 19q13.41 [CytoView hg38]
Mapping of homologs : NCBIKLK4 [Mapview hg19]  KLK4 [Mapview hg38]
OMIM204700   603767   
Gene and transcription
Genbank (Entrez)AF113140 AF126401 AF259964 AF259965 AF259966
RefSeq transcript (Entrez)NM_001302961 NM_004917
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KLK4
Cluster EST : UnigeneHs.218366 [ NCBI ]
CGAP (NCI)Hs.218366
Alternative Splicing GalleryENSG00000167749
Gene ExpressionKLK4 [ NCBI-GEO ]   KLK4 [ EBI - ARRAY_EXPRESS ]   KLK4 [ SEEK ]   KLK4 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9622
GTEX Portal (Tissue expression)KLK4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y5K2   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y5K2  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y5K2
Splice isoforms : SwissVarQ9Y5K2
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
PhosPhoSitePlusQ9Y5K2
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)KLK4
DMDM Disease mutations9622
Blocks (Seattle)KLK4
PDB (SRS)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
PDB (PDBSum)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
PDB (IMB)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
PDB (RSDB)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
Structural Biology KnowledgeBase2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
SCOP (Structural Classification of Proteins)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
CATH (Classification of proteins structures)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA   
SuperfamilyQ9Y5K2
Human Protein AtlasENSG00000167749
Peptide AtlasQ9Y5K2
HPRD04793
IPIIPI00001559   IPI00644676   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y5K2
IntAct (EBI)Q9Y5K2
FunCoupENSG00000167749
BioGRIDKLK4
STRING (EMBL)KLK4
ZODIACKLK4
Ontologies - Pathways
QuickGOQ9Y5K2
Ontology : AmiGOserine-type endopeptidase activity  protein binding  extracellular region  proteolysis  serine-type peptidase activity  biomineral tissue development  metal ion binding  amelogenesis  
Ontology : EGO-EBIserine-type endopeptidase activity  protein binding  extracellular region  proteolysis  serine-type peptidase activity  biomineral tissue development  metal ion binding  amelogenesis  
NDEx NetworkKLK4
Atlas of Cancer Signalling NetworkKLK4
Wikipedia pathwaysKLK4
Orthology - Evolution
OrthoDB9622
GeneTree (enSembl)ENSG00000167749
Phylogenetic Trees/Animal Genes : TreeFamKLK4
HOVERGENQ9Y5K2
HOGENOMQ9Y5K2
Homologs : HomoloGeneKLK4
Homology/Alignments : Family Browser (UCSC)KLK4
Gene fusions - Rearrangements
Fusion : MitelmanKAT6A/KLK4 [8p11.21/19q13.41]  [t(8;19)(p11;q13)]  
Fusion: TCGAKAT6A 8p11.21 KLK4 19q13.41 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK4
dbVarKLK4
ClinVarKLK4
1000_GenomesKLK4 
Exome Variant ServerKLK4
ExAC (Exome Aggregation Consortium)KLK4 (select the gene name)
Genetic variants : HAPMAP9622
Genomic Variants (DGV)KLK4 [DGVbeta]
DECIPHERKLK4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLK4 
Mutations
ICGC Data PortalKLK4 
TCGA Data PortalKLK4 
Broad Tumor PortalKLK4
OASIS PortalKLK4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKLK4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLK4
DgiDB (Drug Gene Interaction Database)KLK4
DoCM (Curated mutations)KLK4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK4 (select a term)
intoGenKLK4
NCG5 (London)KLK4
Cancer3DKLK4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM204700    603767   
Orphanet14606   
MedgenKLK4
Genetic Testing Registry KLK4
NextProtQ9Y5K2 [Medical]
TSGene9622
GENETestsKLK4
Target ValidationKLK4
Huge Navigator KLK4 [HugePedia]
snp3D : Map Gene to Disease9622
BioCentury BCIQKLK4
ClinGenKLK4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9622
Chemical/Pharm GKB GenePA30154
Clinical trialKLK4
Miscellaneous
canSAR (ICR)KLK4 (select the gene name)
Probes
Litterature
PubMed67 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLK4
EVEXKLK4
GoPubMedKLK4
iHOPKLK4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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