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KLK5 (Kallikrein-related peptidase 5)

Identity

Other namesEC 3.4.21
HSCTE
KLK-L2
KLKL2
SCTE
HGNC (Hugo) KLK5
LocusID (NCBI) 25818
Location 19q13.41
Location_base_pair Starts at 51446559 and ends at 51456344 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Telomere to centromere

DNA/RNA

Description The KLK5 gene is approximately 9.5 Kb in length, consisting of 6 exons (5 of them are coding exons) and 5 introns.
Transcription Five alternatively spliced variants have been identified for the KLK5 gene. These variants differ in the number and length of the 5' untranslated exons and/or the last two coding exons. Tissue-specific expression of these variants is regulated by multiple promoters located in the first exon of each isoform. KLK5 splice variants were found to be differentially expressed, at the mRNA level, in ovarian, breast and prostate cancers.
Pseudogene None identified.

Protein

Description Full-length KLK5 is formed of 293 amino acids. It is composed of a signal peptide (29 amino acids), followed by an activation peptide (37 amino acids) and the mature chain (227 amino acids), with 4 potential N-linked glycosylation sites. The positions of the catalytic triad of serine proteases is conserved. KLK5 is synthesized as a full-length protein intracellularly. In the secretary pathway, the signal peptide is cleaved and the zymogen is released outside the cells. Upon activation, the propeptide is removed to generate the mature active protein. In serum and ascites fluid, in addition to the free (approximately 40 kDa) form, KLK5 forms complexes with alpha(1)-antitrypsin and alpha(2)-macroglobulin.
Expression At the mRNA level, KLK5 is expressed in a variety of tissues, mainly the testis, brain, breast, thyroid and salivary glands. The KLK5 protein is expressed at higher levels in the skin, salivary gland, testis and female genital organs. KLK5 has also been identified in many biological fluids, including vaginal secretions, breast milk and seminal plasma. Many fetal tissues, including bone, skin, thymus and kidney also express KLK5.
Localisation KLK5 is a secreted protein.
Function KLK5 is a secreted serine protease. The physiological functions of KLK5 are not fully understood. The KLK5 protein was originally identified from a keratinocyte library and was purified from the stratum corneum of the human skin. It was found to have a trypsin-like enzymatic activity with strong preference for Arg over Lys in the P1 position. Evidence exists that it plays a role in skin desquamation. KLK5 can also digest extracellular matrix components, collagens type I, II, III, IV, fibronectin, and laminin, and can potentially release angiostatin from plasminogen, and "cystatin-like domain 3" from low molecular weight kininogen, and fibrinopeptide B and peptide beta15-42 from the B beta chain of fibrinogen. The KLK5 protein has been shown to activate another kallikrein, KLK7, and was found to be under steroid hormonal regulation in cancer cell lines. It has been recently shown that KLK5 is differentially expressed in a number of malignancies, including ovarian, breast and prostate cancers, but the mechanisms of its involvement in cancer have yet to be determined.
Homology The human KLK5 protein sequence shares 40-70 % homology with other members of the human tissue kallikreins, and 70% identity with that of the mouse orthologue.

Mutations

Note No germinal or somatic mutations are identified to be associated with cancer so far.

Implicated in

Entity Ovarian cancer
Disease Higher KLK5 concentrations were found in the serum of 69% of patients with ovarian cancer. The KLK5 protein was found to be elevated in 55% of ovarian cancer tissues compared to normal. Also, KLK5 mRNA is significantly elevated in ovarian cancer, specially serous type. Ovarian cancer ascites contains higher levels, as compared to benign effusions and ascites from other cancer types. Two KLK5 splice variants are upregulated in ovarian cancer tissues compared to normal.
Prognosis The KLK5 mRNA and protein are markers of unfavorable prognosis in ovarian cancer, being overexpressed in late stage and higher grade tumors, and associated with shorter DFS and OS. In addition, the KLK5 protein was shown to be an independent indicator of poor prognosis in patients with high-grade tumors and optimal debulking success.
Cytogenetics No cytogenetic abnormalities are identified so far.
Hybrid/Mutated Gene None identified.
  
Entity Breast cancer
Disease Higher concentrations of KLK5 were found in the serum of 49% of patients with breast cancer. KLK5 splice variant 2 is downregulated in breast cancer compared to normal.
Prognosis The KLK5 mRNA transcript was found to be an indicator of unfavorable prognosis, being overexpressed in node-positive patients with ER-negative tumors. It is independently associated with decreased DFS and OS, and it is an independent indicator of shorter DFS and OS in node-positive patients.
Cytogenetics No cytogenetic abnormalities are identified so far.
Hybrid/Mutated Gene None identified.
  
Entity Prostate cancer
Disease KLK5 mRNA is downregulated in cancer vs normal prostatic tissues.
Prognosis KLK5 mRNA is a favorable prognostic maker, with higher levels associated with low grade tumors and low Gleason score.
Cytogenetics No cytogenetic abnormalities are identified so far.
Hybrid/Mutated Gene None identified.
  
Entity Testicular cancer
Disease KLK5 mRNA is downregulated in cancer vs normal testicular tissues.
Prognosis KLK5 mRNA is a marker of favorable prognosis, overexpressed in smaller, early stage non-seminomas.
Cytogenetics No cytogenetic abnormalities are identified so far.
Hybrid/Mutated Gene None identified.
  
Entity Non-small cell lung carcinoma
Disease Serum KLK5 levels are lower in lung cancer compared to normal and can be used as part of a multiparametric panel for diagnosis.
Prognosis None identified.
Cytogenetics No cytogenetic abnormalities are identified so far.
Hybrid/Mutated Gene None identified.
  
Entity Urinary bladder carcinoma
Disease None identified.
Prognosis Increased expression of KLK5 was frequently observed in invasive tumors (pT2-pT4) compared with superficial tumors (pTa, pT1).
Cytogenetics Copy number gain was observed in transitional cell carcinoma.
Hybrid/Mutated Gene None identified.
  

Breakpoints

Note None identified.

External links

Nomenclature
HGNC (Hugo)KLK5   6366
Cards
AtlasKLK5ID41085ch19q13
Entrez_Gene (NCBI)KLK5  25818  kallikrein-related peptidase 5
GeneCards (Weizmann)KLK5
Ensembl (Hinxton)ENSG00000167754 [Gene_View]  chr19:51446559-51456344 [Contig_View]  KLK5 [Vega]
ICGC DataPortalENSG00000167754
cBioPortalKLK5
AceView (NCBI)KLK5
Genatlas (Paris)KLK5
WikiGenes25818
SOURCE (Princeton)NM_001077491 NM_001077492 NM_012427
Genomic and cartography
GoldenPath (UCSC)KLK5  -  19q13.41   chr19:51446559-51456344 -  19q13.33   [Description]    (hg19-Feb_2009)
EnsemblKLK5 - 19q13.33 [CytoView]
Mapping of homologs : NCBIKLK5 [Mapview]
OMIM605643   
Gene and transcription
Genbank (Entrez)AF168768 AF435980 AF435981 AK223421 AY279380
RefSeq transcript (Entrez)NM_001077491 NM_001077492 NM_012427
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011109 NW_001838498 NW_004929415
Consensus coding sequences : CCDS (NCBI)KLK5
Cluster EST : UnigeneHs.50915 [ NCBI ]
CGAP (NCI)Hs.50915
Alternative Splicing : Fast-db (Paris)GSHG0016036
Alternative Splicing GalleryENSG00000167754
Gene ExpressionKLK5 [ NCBI-GEO ]     KLK5 [ SEEK ]   KLK5 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y337 (Uniprot)
NextProtQ9Y337  [Medical]
With graphics : InterProQ9Y337
Splice isoforms : SwissVarQ9Y337 (Swissvar)
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)TRYPSIN_DOM (PS50240)    TRYPSIN_HIS (PS00134)    TRYPSIN_SER (PS00135)   
Domains : Interpro (EBI)Peptidase_S1 [organisation]   Peptidase_S1_AS [organisation]   Peptidase_S1A [organisation]   Trypsin-like_Pept_dom [organisation]  
Related proteins : CluSTrQ9Y337
Domain families : Pfam (Sanger)Trypsin (PF00089)   
Domain families : Pfam (NCBI)pfam00089   
Domain families : Smart (EMBL)Tryp_SPc (SM00020)  
DMDM Disease mutations25818
Blocks (Seattle)Q9Y337
PDB (SRS)2PSX    2PSY   
PDB (PDBSum)2PSX    2PSY   
PDB (IMB)2PSX    2PSY   
PDB (RSDB)2PSX    2PSY   
Human Protein AtlasENSG00000167754 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ9Y337
HPRD05732
IPIIPI00032464   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y337
IntAct (EBI)Q9Y337
FunCoupENSG00000167754
BioGRIDKLK5
InParanoidQ9Y337
Interologous Interaction database Q9Y337
IntegromeDBKLK5
STRING (EMBL)KLK5
Ontologies - Pathways
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular space  proteolysis  peptidase activity  serine-type peptidase activity  epidermis development  positive regulation of G-protein coupled receptor protein signaling pathway  epidermal lamellar body  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular space  proteolysis  peptidase activity  serine-type peptidase activity  epidermis development  positive regulation of G-protein coupled receptor protein signaling pathway  epidermal lamellar body  
Protein Interaction DatabaseKLK5
Wikipedia pathwaysKLK5
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)KLK5
snp3D : Map Gene to Disease25818
SNP (GeneSNP Utah)KLK5
SNP : HGBaseKLK5
Genetic variants : HAPMAPKLK5
Exome VariantKLK5
1000_GenomesKLK5 
ICGC programENSG00000167754 
Somatic Mutations in Cancer : COSMICKLK5 
CONAN: Copy Number AnalysisKLK5 
Mutations and Diseases : HGMDKLK5
Mutations and Diseases : intOGenKLK5
Genomic VariantsKLK5  KLK5 [DGVbeta]
dbVarKLK5
ClinVarKLK5
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM605643   
MedgenKLK5
GENETestsKLK5
Disease Genetic AssociationKLK5
Huge Navigator KLK5 [HugePedia]  KLK5 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneKLK5
Homology/Alignments : Family Browser (UCSC)KLK5
Phylogenetic Trees/Animal Genes : TreeFamKLK5
Chemical/Protein Interactions : CTD25818
Chemical/Pharm GKB GenePA30155
Clinical trialKLK5
Cancer Resource (Charite)ENSG00000167754
Other databases
Probes
Litterature
PubMed52 Pubmed reference(s) in Entrez
CoreMineKLK5
iHOPKLK5
OncoSearchKLK5

Bibliography

Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis inovarian cancer.
Kim H, Scorilas A, Katsaros D, Yousef GM, Massobrio M, Fracchioli S, Piccinno R, Gordini G, Diamandis EP.
Br J Cancer. 2001; 84: 643-650.
PMID 11237385
 
Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues.
Yousef GM, Obiezu CV, Jung K, Stephan C, Scorilas A, Diamandis EP.
Urology. 2002; 60: 714-718.
PMID 12385949
 
Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues.
Yousef GM, Scorilas A, Chang A, Rendl L, Diamandis M, Jung K, Diamandis EP.
Prostate. 2002; 51: 126-132.
PMID 11948967
 
Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer.
Yousef GM, Scorilas A, Kyriakopoulou LG, Rendl L, Diamandis M, Ponzone R, Biglia N, Giai M, Roagna R, Sismondi P, Diamandis EP.
Clin Chem. 2002; 48: 1241-1250.
PMID 12142380
 
Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers.
Dong Y, Kaushal A, Brattsand M, Nicklin J, Clements JA.
Clin Cancer Res. 2003: 1710-1720.
PMID 12738725
 
The human kallikrein protein 5 (hK5) is enzymatically active, glycosylated and forms complexes with two protease inhibitors in ovarian cancer fluids.
Yousef GM, Kapadia C, Polymeris ME, Borgono C, Hutchinson S, Wasney GA, Soosaipillai A, Diamandis EP.
Biochim Biophys Acta. 2003; 1628(2): 88-96.
PMID 12890555
 
Human kallikrein 5: a potential novel serum biomarker for breast and ovarian cancer.
Yousef GM, Polymeris ME, Grass L, Soosaipillai A, Chan PC, Scorilas A, Borgoņo C, Harbeck N, Schmalfeldt B, Dorn J, Schmitt M, Diamandis EP.
Cancer Res. 2003; 63: 3958-3965.
PMID 12873991
 
Parallel overexpression of seven kallikrein genes in ovarian cancer.
Yousef GM, Polymeris ME, Yacoub GM, Scorilas A, Soosaipillai A, Popalis C, Fracchioli S, Katsaros D, Diamandis EP.
Cancer Res. 2003; 63: 2223-2227.
PMID 12727843
 
Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer.
Kurlender L, Yousef GM, Memari N, Robb JD, Michael IP, Borgoņo C, Katsaros D, Stephan C, Jung K, Diamandis EP.
Tumour Biol. 2004; 25: 149-156.
PMID 15361712
 
The kallikrein gene 5 splice variant 2 is a new biomarker for breast and ovarian cancer.
Yousef GM, White NM, Kurlender L, Michael I, Memari N, Robb JD, Katsaros D, Stephan C, Jung K, Diamandis EP.
Tumour Biol. 2004; 25: 221-227.
PMID 15627884
 
Kallikrein gene downregulation in breast cancer.
Yousef GM, Yacoub GM, Polymeris ME, Popalis C, Soosaipillai A, Diamandis EP.
Br J Cancer. 2004; 90: 167-172.
PMID 14710225
 
Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression.
Michael IP, Sotiropoulou G, Pampalakis G, Magklara A, Ghosh M, Wasney G, Diamandis EP.
J Biol Chem. 2005; 280: 14628-14635.
PMID 15713679
 
KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.
Planque C, de Monte M, Guyetant S, Rollin J, Desmazes C, Panel V, Lemarié E, Courty Y.
Biochem Biophys Res Commun. 2005; 329: 1260-1266.
PMID 15766562
 
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, Krüger A, Magdolen V.
Biol Chem. 2006; 387: 807-811.
PMID 16800744
 
Distribution of 15 human kallikreins in tissues and biological fluids.
Shaw JL, Diamandis EP.
Clin Chem. 2007; 53: 1423-32.
PMID 17573418
 
Association of KLK5 overexpression with invasiveness of urinary bladder carcinoma cells.
Shinoda Y, Kozaki K, Imoto I, Obara W, Tsuda H, Mizutani Y, Shuin T, Fujioka T, Miki T, Inazawa J.
Cancer Sci. 2007; 98: 1078-1086.
PMID 17459052
 
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; 14: 1355-1362.
PMID 18316555
 
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Contributor(s)

Written06-2008George M Yousef, Eleftherios P Diamandis
Department of Laboratory Medicine,St Michael's Hospital,30 Bond Street, Toronto, ON, M5B 1W8, Canada, (GMY); Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 6th Floor, Room 6-201, Box 32, 60 Murray Street, Toronto, Ontario, Canada, M5T 3L9 (EPD)

Citation

This paper should be referenced as such :
Yousef, GM ; Diamandis, EP
KLK5 (Kallikrein-related peptidase 5)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(5):357-359.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/KLK5ID41085ch19q13.html

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indexed on : Tue Aug 26 15:24:38 CEST 2014

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