Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   
X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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 (NCBI)ARM1
EMSP
EMSP1
KLK-L1
MGC116827
MGC116828
Prostase
PRSS17
PSTS
HGNC (Hugo) KLK4
HGNC Alias symbEMSP
EMSP1
PSTS
KLK-L1
HGNC Alias nameenamel matrix serine proteinase 1
HGNC Previous namePRSS17
HGNC Previous name"kallikrein 4 (prostase, enamel matrix, prostate)"
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 GRCh38/hg38-Dec_2013)  [Mapping KLK4.png]
Local_order Telomere to centromere.
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
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.
  

Bibliography

The genetic basis of inherited anomalies of the teeth. Part 1: clinical and molecular aspects of non-syndromic dental disorders.
Bailleul-Forestier I, Molla M, Verloes A, Berdal A.
Eur J Med Genet. 2008 Jul-Aug;51(4):273-91. Epub 2008 Mar 26. Review
PMID 18499550
 
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
 
Kallikreins as microRNA targets: an in silico and experimental-based analysis.
Chow TF, Crow M, Earle T, El-Said H, Diamandis EP, Yousef GM.
Biol Chem. 2008 Jun;389(6):731-8.
PMID 18627289
 
The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions.
Clements J, Hooper J, Dong Y, Harvey T.
Biol Chem. 2001 Jan;382(1):5-14. Review
PMID 11258672
 
Characterization of KLK4 expression and detection of KLK4-specific antibody in prostate cancer patient sera.
Day CH, Fanger GR, Retter MW, Hylander BL, Penetrante RB, Houghton RL, Zhang X, McNeill PD, Filho AM, Nolasco M, Badaro R, Cheever MA, Reed SG, Dillon DC, Watanabe Y.
Oncogene. 2002 Oct 10;21(46):7114-20.
PMID 12370833
 
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7.
Debela M, Beaufort N, Magdolen V, Schechter NM, Craik CS, Schmitt M, Bode W, Goettig P.
Biol Chem. 2008 Jun;389(6):623-32. Review
PMID 18627343
 
Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms.
Dong Y, Bui LT, Odorico DM, Tan OL, Myers SA, Samaratunga H, Gardiner RA, Clements JA.
Endocr Relat Cancer. 2005 Dec;12(4):875-89.
PMID 16322328
 
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
 
In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families.
Elliott MB, Irwin DM, Diamandis EP.
Genomics. 2006 Nov;88(5):591-9. Epub 2006 Jul 7.
PMID 16829021
 
Porcine endometrial and conceptus tissue kallikrein 1, 4, 11, and 14 gene expression.
Fernando SC, Buck JS, Ashworth MD, Ross JW, Geisert RD, DeSilva U.
Reproduction. 2006 Dec;132(6):939-47.
PMID 17127754
 
Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region.
Gan L, Lee I, Smith R, Argonza-Barrett R, Lei H, McCuaig J, Moss P, Paeper B, Wang K.
Gene. 2000 Oct 17;257(1):119-30.
PMID 11054574
 
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
 
Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects.
Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, Ozdemir D, Firatli S, Aren G, Firatli E.
J Med Genet. 2003 Dec;40(12):900-6.
PMID 14684688
 
Localization of EMSP1 expression during tooth formation and cloning of mouse cDNA.
Hu JC, Ryu OH, Chen JJ, Uchida T, Wakida K, Murakami C, Jiang H, Qian Q, Zhang C, Ottmers V, Bartlett JD, Simmer JP.
J Dent Res. 2000 Jan;79(1):70-6.
PMID 10690663
 
Developmental biology and genetics of dental malformations.
Hu JC, Simmer JP.
Orthod Craniofac Res. 2007 May;10(2):45-52. Review
PMID 17552940
 
Enamelysin and kallikrein-4 mRNA expression in developing mouse molars.
Hu JC, Sun X, Zhang C, Liu S, Bartlett JD, Simmer JP.
Eur J Oral Sci. 2002 Aug;110(4):307-15.
PMID 12206593
 
Proteomics and genetics of dental enamel.
Hu JC, Yamakoshi Y, Yamakoshi F, Krebsbach PH, Simmer JP.
Cells Tissues Organs. 2005;181(3-4):219-31.
PMID 16612087
 
Characterization of the mouse and human PRSS17 genes, their relationship to other serine proteases, and the expression of PRSS17 in developing mouse incisors.
Hu JC, Zhang C, Sun X, Yang Y, Cao X, Ryu O, Simmer JP.
Gene. 2000 Jun 13;251(1):1-8.
PMID 10863090
 
Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation.
Hural JA, Friedman RS, McNabb A, Steen SS, Henderson RA, Kalos M.
J Immunol. 2002 Jul 1;169(1):557-65.
PMID 12077288
 
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.
Cancer Res. 2007 Jun 1;67(11):5221-30.
PMID 17545602
 
Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages.
Komatsu N, Takata M, Otsuki N, Toyama T, Ohka R, Takehara K, Saijoh K.
J Invest Dermatol. 2003 Sep;121(3):542-9.
PMID 12925213
 
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
 
Epithelial-mesenchymal transition in prostate cancer and the potential role of kallikrein serine proteases.
Lawrence MG, Veveris-Lowe TL, Whitbread AK, Nicol DL, Clements JA.
Cells Tissues Organs. 2007;185(1-3):111-5. Review
PMID 17587816
 
Mutational spectrum of FAM83H: the C-terminal portion is required for tooth enamel calcification.
Lee SK, Hu JC, Bartlett JD, Lee KE, Lin BP, Simmer JP, Kim JW.
Hum Mutat. 2008 May 16;29(8):E95-E99. [Epub ahead of print]
PMID 18484629
 
Functions of KLK4 and MMP-20 in dental enamel formation.
Lu Y, Papagerakis P, Yamakoshi Y, Hu JC, Bartlett JD, Simmer JP.
Biol Chem. 2008 Jun;389(6):695-700. Review
PMID 18627287
 
Specific increase of human kallikrein 4 mRNA and protein levels in breast cancer stromal cells.
Mange A, Desmetz C, Berthes ML, Maudelonde T, Solassol J.
Biochem Biophys Res Commun. 2008 Oct 10;375(1):107-12. Epub 2008 Aug 5.
PMID 18687310
 
Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries.
Matsumura M, Bhatt AS, Andress D, Clegg N, Takayama TK, Craik CS, Nelson PS.
Prostate. 2005 Jan 1;62(1):1-13.
PMID 15389820
 
Intron retention: a common splicing event within the human kallikrein gene family.
Michael IP, Kurlender L, Memari N, Yousef GM, Du D, Grass L, Stephan C, Jung K, Diamandis EP.
Clin Chem. 2005 Mar;51(3):506-15. Epub 2005 Jan 13.
PMID 15650036
 
Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases.
Mukai S, Fukushima T, Naka D, Tanaka H, Osada Y, Kataoka H.
FEBS J. 2008 Mar;275(5):1003-17. Epub 2008 Jan 25.
PMID 18221492
 
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.
Myers SA, Clements JA.
J Clin Endocrinol Metab. 2001 May;86(5):2323-6.
PMID 11344246
 
Relative levels of mRNA encoding enamel proteins in enamel organ epithelia and odontoblasts.
Nagano T, Oida S, Ando H, Gomi K, Arai T, Fukae M.
J Dent Res. 2003 Dec;82(12):982-6.
PMID 14630899
 
Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression.
Nelson PS, Gan L, Ferguson C, Moss P, Gelinas R, Hood L, Wang K.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3114-9.
PMID 10077646
 
Human tissue kallikrein gene family: applications in cancer.
Obiezu CV, Diamandis EP.
Cancer Lett. 2005 Jun 16;224(1):1-22. Review
PMID 15911097
 
Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids.
Obiezu CV, Shan SJ, Soosaipillai A, Luo LY, Grass L, Sotiropoulou G, Petraki CD, Papanastasiou PA, Levesque MA, Diamandis EP.
Clin Chem. 2005 Aug;51(8):1432-42. Epub 2005 Jun 16.
PMID 15961548
 
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
 
Organization and evolution of the glandular kallikrein locus in Mus musculus.
Olsson AY, Lundwall A.
Biochem Biophys Res Commun. 2002 Nov 29;299(2):305-11.
PMID 12437987
 
Premature stop codon in MMP20 causing amelogenesis imperfecta.
Papagerakis P, Lin HK, Lee KY, Hu Y, Simmer JP, Bartlett JD, Hu JC.
J Dent Res. 2008 Jan;87(1):56-9.
PMID 18096894
 
Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG.
Pavlic A, Petelin M, Battelino T.
Arch Oral Biol. 2007 Mar;52(3):209-17. Epub 2006 Nov 27.
PMID 17125728
 
A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma.
Planque C, Li L, Zheng Y, Soosaipillai A, Reckamp K, Chia D, Diamandis EP, Goodglick L.
Clin Cancer Res. 2008 Mar 1;14(5):1355-62.
PMID 18316555
 
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
 
Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression.
Ramsay AJ, Dong Y, Hunt ML, Linn M, Samaratunga H, Clements JA, Hooper JD.
J Biol Chem. 2008 May 2;283(18):12293-304. Epub 2008 Feb 28.
PMID 18308730
 
Porcine kallikrein-4 activation, glycosylation, activity, and expression in prokaryotic and eukaryotic hosts.
Ryu O, Hu JC, Yamakoshi Y, Villemain JL, Cao X, Zhang C, Bartlett JD, Simmer JP.
Eur J Oral Sci. 2002 Oct;110(5):358-65.
PMID 12664466
 
Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta.
Santos MC, Hart PS, Ramaswami M, Kanno CM, Hart TC, Line SR.
Head Face Med. 2007 Jan 31;3:8.
PMID 17266769
 
Enamel matrix serine proteinase 1: stage-specific expression and molecular modeling.
Scully JL, Bartlett JD, Chaparian MG, Fukae M, Uchida T, Xue J, Hu CC, Simmer JP.
Connect Tissue Res. 1998;39(1-3):111-22; discussion 141-9.
PMID 11062993
 
Purification, characterization, and cloning of enamel matrix serine proteinase 1.
Simmer JP, Fukae M, Tanabe T, Yamakoshi Y, Uchida T, Xue J, Margolis HC, Shimizu M, DeHart BC, Hu CC, Bartlett JD.
J Dent Res. 1998 Feb;77(2):377-86.
PMID 9465170
 
Expression, structure, and function of enamel proteinases.
Simmer JP, Hu JC.
Connect Tissue Res. 2002;43(2-3):441-9. Review
PMID 12489196
 
Genes and related proteins involved in amelogenesis imperfecta.
Stephanopoulos G, Garefalaki ME, Lyroudia K.
J Dent Res. 2005 Dec;84(12):1117-26. Review
PMID 16304440
 
Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4.
Stephenson SA, Verity K, Ashworth LK, Clements JA.
J Biol Chem. 1999 Aug 13;274(33):23210-4.
PMID 10438493
 
Enamel proteases reduce amelogenin-apatite binding.
Sun Z, Fan D, Fan Y, Du C, Moradian-Oldak J.
J Dent Res. 2008 Dec;87(12):1133-7.
PMID 19029081
 
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.
Takayama TK, McMullen BA, Nelson PS, Matsumura M, Fujikawa K.
Biochemistry. 2001 Dec 18;40(50):15341-8.
PMID 11735417
 
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.
Endocr Relat Cancer. 2005 Sep;12(3):631-43.
PMID 16172196
 
[Exclusion of candidate genes in a family with amelogenesis imperfecta]
Wang XJ, Ji P, Guo HM, Yi XZ.
Hua Xi Kou Qiang Yi Xue Za Zhi. 2007 Jun;25(3):249-52.
PMID 17629198
 
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
 
Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4.
Wright JT, Hart TC, Hart PS, Simmons D, Suggs C, Daley B, Simmer J, Hu J, Bartlett JD, Li Y, Yuan ZA, Seow WK, Gibson CW.
Cells Tissues Organs. 2009;189(1-4):224-9. Epub 2008 Aug 19.
PMID 18714142
 
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
 
Kallikrein 4 is associated with paclitaxel resistance in ovarian cancer.
Xi Z, Kaern J, Davidson B, Klokk TI, Risberg B, Trope C, Saatcioglu F.
Gynecol Oncol. 2004 Jul;94(1):80-5.
PMID 15262123
 
Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer.
Xi Z, Klokk TI, Korkmaz K, Kurys P, Elbi C, Risberg B, Danielsen H, Loda M, Saatcioglu F.
Cancer Res. 2004 Apr 1;64(7):2365-70.
PMID 15059887
 
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
 
Activation profiles and regulatory cascades of the human kallikrein-related peptidases.
Yoon H, Laxmikanthan G, Lee J, Blaber SI, Rodriguez A, Kogot JM, Scarisbrick IA, Blaber M.
J Biol Chem. 2007 Nov 2;282(44):31852-64. Epub 2007 Sep 6.
PMID 17823117
 
Prostase/KLK-L1 is a new member of the human kallikrein gene family, is expressed in prostate and breast tissues, and is hormonally regulated.
Yousef GM, Obiezu CV, Luo LY, Black MH, Diamandis EP.
Cancer Res. 1999 Sep 1;59(17):4252-6.
PMID 10485467
 

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 ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(8;19)(p11;q13) KAT6A/KLK4

External links

Nomenclature
HGNC (Hugo)KLK4   6365
Cards
AtlasKLK4ID41084ch19q13
Entrez_Gene (NCBI)KLK4    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]  ENSG00000167749 [Sequence]  chr19:50906352-50910738 [Contig_View]  KLK4 [Vega]
ICGC DataPortalENSG00000167749
TCGA cBioPortalKLK4
AceView (NCBI)KLK4
Genatlas (Paris)KLK4
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)
GoldenPathKLK4 - 19q13.41 [CytoView hg19]  KLK4 - 19q13.41 [CytoView hg38]
ImmunoBaseENSG00000167749
genome Data Viewer NCBIKLK4 [Mapview hg19]  
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
Alternative Splicing GalleryENSG00000167749
Gene ExpressionKLK4 [ NCBI-GEO ]   KLK4 [ EBI - ARRAY_EXPRESS ]   KLK4 [ SEEK ]   KLK4 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK4 [ Firebrowse - Broad ]
GenevisibleExpression of KLK4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9622
GTEX Portal (Tissue expression)KLK4
Human Protein AtlasENSG00000167749-KLK4 [pathology]   [cell]   [tissue]
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 ]   [ MEROPS ]
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
Blocks (Seattle)KLK4
PDB (RSDB)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
PDB Europe2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
PDB (PDBSum)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
PDB (IMB)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
Structural Biology KnowledgeBase2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
SCOP (Structural Classification of Proteins)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
CATH (Classification of proteins structures)2BDG    2BDH    2BDI    4K1E    4K8Y    4KEL    4KGA    6KBR    6NVB    6O21   
SuperfamilyQ9Y5K2
Human Protein Atlas [tissue]ENSG00000167749-KLK4 [tissue]
Peptide AtlasQ9Y5K2
HPRD04793
IPIIPI00001559   IPI00644676   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y5K2
IntAct (EBI)Q9Y5K2
BioGRIDKLK4
STRING (EMBL)KLK4
ZODIACKLK4
Ontologies - Pathways
QuickGOQ9Y5K2
Ontology : AmiGOserine-type endopeptidase activity  protein binding  extracellular region  proteolysis  serine-type peptidase activity  extracellular matrix disassembly  secretory granule  biomineral tissue development  metal ion binding  amelogenesis  amelogenesis  
Ontology : EGO-EBIserine-type endopeptidase activity  protein binding  extracellular region  proteolysis  serine-type peptidase activity  extracellular matrix disassembly  secretory granule  biomineral tissue development  metal ion binding  amelogenesis  amelogenesis  
NDEx NetworkKLK4
Atlas of Cancer Signalling NetworkKLK4
Wikipedia pathwaysKLK4
Orthology - Evolution
OrthoDB9622
GeneTree (enSembl)ENSG00000167749
Phylogenetic Trees/Animal Genes : TreeFamKLK4
HOGENOMQ9Y5K2
Homologs : HomoloGeneKLK4
Homology/Alignments : Family Browser (UCSC)KLK4
Gene fusions - Rearrangements
Fusion : MitelmanKAT6A/KLK4 [8p11.21/19q13.41]  
Fusion PortalKAT6A 8p11.21 KLK4 19q13.41 BRCA
Fusion : Fusion_HubBCAM--KLK4    CELA2A--KLK4    KAT6A--KLK4    KIF1C--KLK4    KLK3--KLK4    KLK4--BCAM    KLK4--KLKP1    KLK4--PRSS36    KLK4--ZNF827    KLKP1--KLK4   
Fusion : QuiverKLK4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK4 [hg38]
dbVarKLK4
ClinVarKLK4
MonarchKLK4
1000_GenomesKLK4 
Exome Variant ServerKLK4
GNOMAD BrowserENSG00000167749
Varsome BrowserKLK4
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]  
Somatic Mutations in Cancer : COSMIC3DKLK4
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
NCG6 (London) select KLK4
Cancer3DKLK4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM204700    603767   
Orphanet14606   
DisGeNETKLK4
MedgenKLK4
Genetic Testing Registry KLK4
NextProtQ9Y5K2 [Medical]
GENETestsKLK4
Target ValidationKLK4
Huge Navigator KLK4 [HugePedia]
ClinGenKLK4
Clinical trials, drugs, therapy
MyCancerGenomeKLK4
Protein Interactions : CTD
Pharm GKB GenePA30154
PharosQ9Y5K2
Clinical trialKLK4
Miscellaneous
canSAR (ICR)KLK4 (select the gene name)
HarmonizomeKLK4
DataMed IndexKLK4
Probes
Litterature
PubMed88 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXKLK4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Feb 19 17:53:32 CET 2021
Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.