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KLK4 (kallikrein-related peptidase 4)

Identity

Other namesARM1
EMSP
EMSP1
KLK-L1
MGC116827
MGC116828
Prostase
PRSS17
PSTS
HGNC (Hugo) KLK4
Location 19q13.33
Location_base_pair Starts at 56101420 and ends at 56105806 bp from pter ( according to hg18-Mar_2006)  [Mapping]
Local_order Telomere to centromere.

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

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.
  

External links

Nomenclature
HGNC (Hugo)KLK4   6365
Entrez_Gene (NCBI)KLK4  9622  kallikrein-related peptidase 4
Cards
AtlasKLK4ID41084ch19q13
GeneCards (Weizmann)KLK4
Ensembl (Hinxton)ENSG00000167749 [Gene_View]  KLK4 [Vega]
AceView (NCBI)KLK4
Genatlas (Paris)KLK4
euGene (Indiana)9622
SOURCE (Stanford)NM_004917
Gene Expression (Array Express) ENSG00000167749
Genomic and cartography
GoldenPath (UCSC)KLK4  -  19q13.33   chr19:56101420-56105806 -  19q13.41   [Description]    (hg18-Mar_2006)
EnsemblKLK4 - 19q13.41 [CytoView]
Mapping of homologs : NCBIKLK4 [Mapview]
OMIM204700   603767   
Gene and transcription
Gene : Genbank (Entrez)AF113140 AF126401 AF259964 AF259965 AF259966
Reference sequence (RefSeq transcript) :SRSNM_004917
Reference transcript : EntrezNM_004917
RefSeq genomic : SRSAC_000062 AC_000151 NC_000019 NG_012154 NT_011109 NW_001838498 NW_927284
RefSeq genomic : EntrezAC_000062 AC_000151 NC_000019 NG_012154 NT_011109 NW_001838498 NW_927284
Consensus coding sequences : CCDS NCBIKLK4
Cluster EST : UnigeneHs.218366 [ SRS ] Hs.218366 [ NCBI ]
Alternative Splicing : Fast-db (Paris)14684
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ9Y5K2 (SRS) Q9Y5K2 (Expasy) Q9Y5K2 (Uniprot)
With graphics : InterProQ9Y5K2
Splice isoforms : VarSplice FASTAQ9Y5K2(VarSplice FASTA)
Domaine pattern : Prosite (SRS)TRYPSIN_DOM (PS50240)    TRYPSIN_HIS (PS00134)    TRYPSIN_SER (PS00135)   
Domain pattern : Prosite (Expaxy)TRYPSIN_DOM (PS50240)    TRYPSIN_HIS (PS00134)    TRYPSIN_SER (PS00135)   
Domains : Interpro (SRS)Peptidase_S1/S6_AS    Peptidase_S1_S6    Peptidase_S1A    Ser/Cys_Pept_Trypsin-like   
Domains : Interpro (EBI)Peptidase_S1/S6_AS    Peptidase_S1_S6    Peptidase_S1A    Ser/Cys_Pept_Trypsin-like   
Related proteins : CluSTrQ9Y5K2
Domain families : Pfam SRSTrypsin (PF00089)   
Domain families : Pfam SangerTrypsin (PF00089)   
Domain families : Pfam NCBIpfam00089   
Domain families : Smart EMBLTryp_SPc (SM00020)  
Blocks (Seattle)Q9Y5K2
Crystal structure of protein : PDB SRS2BDG    2BDH    2BDI   
Crystal structure of protein : PDBSum2BDG    2BDH    2BDI   
Crystal structure of protein : IMB2BDG    2BDH    2BDI   
Crystal structure of protein : PDB RSDB2BDG    2BDH    2BDI   
HPRD04793
Protein Interaction databases
DIP (DOE-UCLA)Q9Y5K2
IntAct (EBI)Q9Y5K2
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIKLK4
SNP : GeneSNP UtahKLK4
SNP : HGBaseKLK4
Genetic variants : HAPMAPKLK4
Somatic Mutations in Cancer : COSMICKLK4 
Mutations and Diseases : HGMDKLK4
Hereditary diseases : OMIM204700    603767   
Hereditary diseases : GENETests204700    603767   
Diseases : Genetic AssociationKLK4
General knowledge
Homologs : HomoloGeneKLK4
Homology/Alignments : Family Browser UCSCKLK4
Phylogenetic Trees/Animal Genes : TreeFamKLK4
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.- [ Enzyme-SRS ]   3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
Chemical/Protein Interactions : CTD9622
Keywords Ontology : AmiGOserine-type endopeptidase activity  extracellular region  proteolysis  peptidase activity  zinc ion binding  metal ion binding  
Keywords Ontology : EGO-EBIserine-type endopeptidase activity  extracellular region  proteolysis  peptidase activity  zinc ion binding  metal ion binding  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Probes
Probes : ImagenesKLK4 Related clones (RZPD - Berlin)
Literature
PubMed37 Pubmed reference(s) in Entrez
PubGeneKLK4

Bibliography

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Characterization of the mouse and human PRSS17 genes, their relationship to other serine proteases, and the expression of PRSS17 in developing mouse incisors.
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An alternatively spliced variant of KLK4 expressed in prostatic tissue.
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The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions.
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Biol Chem. 2001 Jan;382(1):5-14. Review
PMID 11258672
 
Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas.
Dong Y, Kaushal A, Bui L, Chu S, Fuller PJ, Nicklin J, Samaratunga H, Clements JA.
Clin Cancer Res. 2001 Aug;7(8):2363-71.
PMID 11489814
 
Distinctly different gene structure of KLK4/KLK-L1/prostase/ARM1 compared with other members of the kallikrein family: intracellular localization, alternative cDNA forms, and Regulation by multiple hormones.
Korkmaz KS, Korkmaz CG, Pretlow TG, Saatcioglu F.
DNA Cell Biol. 2001 Jul;20(7):435-45.
PMID 11506707
 
Kallikrein 4 (KLK4), a new member of the human kallikrein gene family is up-regulated by estrogen and progesterone in the human endometrial cancer cell line, KLE.
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J Clin Endocrinol Metab. 2001 May;86(5):2323-6.
PMID 11344246
 
Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients.
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Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase.
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Characterization of KLK4 expression and detection of KLK4-specific antibody in prostate cancer patient sera.
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Enamelysin and kallikrein-4 mRNA expression in developing mouse molars.
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Eur J Oral Sci. 2002 Aug;110(4):307-15.
PMID 12206593
 
Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation.
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J Immunol. 2002 Jul 1;169(1):557-65.
PMID 12077288
 
Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry.
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Organization and evolution of the glandular kallikrein locus in Mus musculus.
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Porcine kallikrein-4 activation, glycosylation, activity, and expression in prokaryotic and eukaryotic hosts.
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Expression, structure, and function of enamel proteinases.
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Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects.
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Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages.
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PMID 12925213
 
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PMID 14630899
 
Kallikrein 4 is associated with paclitaxel resistance in ovarian cancer.
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PMID 15262123
 
Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer.
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PMID 15059887
 
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PMID 16612087
 
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PMID 15389820
 
Intron retention: a common splicing event within the human kallikrein gene family.
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Clin Chem. 2005 Mar;51(3):506-15. Epub 2005 Jan 13.
PMID 15650036
 
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PMID 15911097
 
Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids.
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Genes and related proteins involved in amelogenesis imperfecta.
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PMID 16304440
 
Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial-mesenchymal transition (EMT)-like effect in prostate cancer cells.
Veveris-Lowe TL, Lawrence MG, Collard RL, Bui L, Herington AC, Nicol DL, Clements JA.
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PMID 16172196
 
In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families.
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PMID 16829021
 
Porcine endometrial and conceptus tissue kallikrein 1, 4, 11, and 14 gene expression.
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Reproduction. 2006 Dec;132(6):939-47.
PMID 17127754
 
Kallikreins as markers of disseminated tumour cells in ovarian cancer-- a pilot study.
Oikonomopoulou K, Scorilas A, Michael IP, Grass L, Soosaipillai A, Rosen B, Murphy J, Diamandis EP.
Tumour Biol. 2006;27(2):104-14. Epub 2006 Mar 24.
PMID 16557045
 
Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells.
Prezas P, Arlt MJ, Viktorov P, Soosaipillai A, Holzscheiter L, Schmitt M, Talieri M, Diamandis EP, Kruger A, Magdolen V.
Biol Chem. 2006 Jun;387(6):807-11.
PMID 16800744
 
The role of kallikrein-related peptidases in prostate cancer: potential involvement in an epithelial to mesenchymal transition.
Whitbread AK, Veveris-Lowe TL, Lawrence MG, Nicol DL, Clements JA.
Biol Chem. 2006 Jun;387(6):707-14. Review
PMID 16800731
 
The molecular etiologies and associated phenotypes of amelogenesis imperfecta.
Wright JT.
Am J Med Genet A. 2006 Dec 1;140(23):2547-55. Review
PMID 16838342
 
How do enamelysin and kallikrein 4 process the 32-kDa enamelin?
Yamakoshi Y, Hu JC, Fukae M, Yamakoshi F, Simmer JP.
Eur J Oral Sci. 2006 May;114 Suppl 1:45-51; discussion 93-5, 379-80.
PMID 16674662
 
Defining the extended substrate specificity of kallikrein 1-related peptidases.
Borgono CA, Gavigan JA, Alves J, Bowles B, Harris JL, Sotiropoulou G, Diamandis EP.
Biol Chem. 2007 Nov;388(11):1215-25.
PMID 17976015
 
Kallikrein 4 is a potential mediator of cellular interactions between cancer cells and osteoblasts in metastatic prostate cancer.
Gao J, Collard RL, Bui L, Herington AC, Nicol DL, Clements JA.
Prostate. 2007 Mar 1;67(4):348-60.
PMID 17221837
 
Developmental biology and genetics of dental malformations.
Hu JC, Simmer JP.
Orthod Craniofac Res. 2007 May;10(2):45-52. Review
PMID 17552940
 
Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer.
Klokk TI, Kilander A, Xi Z, Waehre H, Risberg B, Danielsen HE, Saatcioglu F.
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Contributor(s)

Written01-2009John Lai, Ying Dong, Judith A Clements
Hormone Dependent Cancer Program, Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia

Citation

This paper should be referenced as such :
Lai J, Dong Y, Clements JA . KLK4 (kallikrein-related peptidase 4). Atlas Genet Cytogenet Oncol Haematol. January 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/KLK4ID41084ch19q13.html

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