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KLK12 (kallikrein-related peptidase 12)

Written2016-09Christos K. Kontos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece /

Abstract Review on KLK12, with data on DNA, on the protein encoded, and where the gene is implicated.

(Note : for Links provided by Atlas : click)


Other namesKLK-L5
HGNC (Hugo) KLK12
LocusID (NCBI) 43849
Atlas_Id 41078
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 51532348 and ends at 51538148 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK12.png]
Local_order Telomere to centromere


  Figure 1. Schematic representation of the KLK12 gene. Exons are shown as boxes and introns as connecting lines. The coding sequences are highlighted as red, while 5' and 3' untranslated regions (UTRs) are shown in white. Numbers inside or outside boxes indicate lengths (nt) of exons and introns, respectively, while numbers in parentheses indicate lengths (aa) of protein isoforms. Arrows show the position of the start codons (ATG) and asterisks (*) denote the position of the stop codons (TAA or TGA). Roman numerals indicate intron phases. The intron phase refers to the location of the intron within the codon; I denotes that the intron occurs after the first nucleotide of the codon, II denotes that the intron occurs after the second nucleotide, and 0 means that the intron occurs between distinct codons. The figure is drawn to scale, except for the introns containing the (//) symbol.
Description The KLK12 gene has a total length of 6.700 nt and consists of 7 exons and 6 intervening introns. The organization of the KLK12 gene is similar to that of the other KLK family members (Yousef et al., 2000). Four different types of genetic polymorphisms have been identified so far: one at a splice-donor site of intron 4 (c.457+2T>C), two in exon 6 (c.618_619delTG:p.Cys206fsX72 and c.735G>A:p.Met245Ile), and one in intron 3. The c.457+2T>C polymorphism was found at a high frequency (allele frequency:0.63), compared to the frequencies of the two polymorphisms in exon 6 (allele frequency:0.01) (Shinmura et al., 2004).
Transcription The KLK12 gene is subjected to alternative splicing, generating three splice variants, which are considered to encode distinct protein isoforms (Kurlender et al., 2005). Each coding splice variant consists of a distinctive exon combination. The predominant transcript, consisting of 945 nt, includes all 7 exons and encodes isoform 1 precursor. The second transcript uses alternate splice sites in the 3' coding region, in comparison with the aforementioned variant, generating a protein with a distinct C-terminus compared to the isoform 1 precursor. The third transcript lacks an exon in the coding region and uses alternate splice sites in the 3' coding region, compared to the first variant, generating a protein with a shorter and distinct C-terminus compared to isoform 1.
Two more splice variants are predicted to be encoded by the KLK12 gene, based on automatic sequence analysis of expressed sequence tags (ESTs). One of them is similar to the third variant; it differs only by having longer 5'- and 3'-untranslated regions (5'-UTR and 3'-UTR). The second one contains a 3'-extended exon 2, which abolishes the original translation start codon (ATG); an alternative start codon located in exon 3 is predicted to be used.
Pseudogene Not identified so far.


  Figure 2. Alignment of amino acid sequences of the precursors of the KLK12 protein isoforms. The three amino acid residues (positions: 62, 108, and 200) constituting the catalytic triad that is required for protease activity are shown in red. The N-terminal signal peptide (positions 1-17) is shown in light blue.
Description The main KLK12 isoform (isoform 1) precursor, designated as the classical one, consists of 254 amino acid residues and has a molecular mass of 25.3 kDa. The N-terminal signal peptide comprises 17 amino acid residues. KLK12 is a secreted trypsin-like serine protease, cleaving peptide bonds after both arginine and lysine (Memari et al., 2007; Yousef et al., 2000). KLK12 protein isoforms are synthesised as inactive precursor zymogens that are cleaved at the position 21 during limited proteolysis to generate their active forms. Three amino acid residues (positions: 62, 108, and 200) constitute the catalytic triad that is required for protease activity. KLK12 isoform 2 has a distinct C-terminus compared to isoform 1, and its precursor form consists of 248 amino acid residues. KLK12 isoform 3 has a shorter and distinct C-terminus compared to isoform 1, and its precursor form consists of 111 amino acid residues.
KLK12 is secreted as an inactive pro-enzyme, which can be self-activated to gain enzymatic activity. Active KLK12 shows trypsin-like activity, but quickly loses its activity due to autodegradation. KLK12 activity can also be rapidly inhibited by zinc ions and by α2-antiplasmin through covalent complex formation. It has been suggested that KLK12 participates in enzymatic cascades involving other KLKs (Memari et al., 2007). KLK12 is able to cleave all six members of the CCN family (CYR61, CTGF, NOV, WISP1, WIPS2, and WISP3) at different proteolytic sites, thus indirectly regulating the bioavailability and activity of several growth factors through processing of their CCN-binding partners (Guillon-Munos et al., 2011). In vivo substrates include also the thrombolytic zymogens plasminogen, urokinase, and plasma kallikrein. Another substrate of KLK12 secreted by the respiratory tract is influenza HA protein (Hamilton and Whittaker, 2013). Furthermore, KLK12 participates in the control of angiogenesis via a PDGFB-dependent paracrine pathway (Kryza et al., 2013; Kryza et al., 2014). On the other hand, the proteolytic activity of KLK12 is inhibited by the action of serine peptidase inhibitor, Kazal type 6 (SPINK6) in the skin (Kantyka et al., 2011).
Expression KLK12 mRNA is primarily expressed in the salivary gland, stomach, uterus trachea, prostate, thymus, lung, colon, brain, breast, and thyroid gland. However, lower levels of KLK12 mRNA expression are found in other tissues too, including testis, pancreas, small intestine, and spinal cord (Yousef et al., 2000).

Implicated in

Entity Prostate cancer
Note KLK12 single nucleotide polymorphism (SNP) rs3865443 is significantly associated with increased risk of prostate cancer; still, this association has been described as marginal (Lose et al., 2013).
Entity Breast cancer
Note KLK12 mRNA expression is downregulated in breast cancer tissues and is upregulated by steroid hormones in breast and prostate cancer cell lines (Talieri et al., 2012; Yousef et al., 2000).
Prognosis KLK12 variant 3 expression is downregulated in breast tumors of small size, high grade, and advanced TNM stage. Moreover, KLK12 variant 3 overexpression is associated with superior disease-free survival (DFS) rates for breast cancer patients, as well as with elevated progesterone receptor (PR) concentration (Talieri et al., 2012).
Entity Gastric cancer
Note Expression of the KLK12 gene is significantly upregulated in gastric cancer tissues, as compared with normal gastric tissues, both at the mRNA and protein level.
Prognosis KLK12 overexpression is significantly associated with lymph node metastasis, histological type, and TNM. Furthermore, patients with gastric tumors showing high KLK12 expression have a significantly worse five-year survival rate than those with tumors with low KLK12 expression (Zhao et al., 2012).
Entity Non-small cell lung cancer
Note KLK12 levels are lower in sera from non-small cell lung cancer patients than in sera from normal controls. Serum KLK12 concentration is likely to be associated with disease stage (Planque et al., 2008).


Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors.
Guillon-Munos A, Oikonomopoulou K, Michel N, Smith CR, Petit-Courty A, Canepa S, Reverdiau P, Heuze-Vourc'h N, Diamandis EP, Courty Y.
J Biol Chem 2011; 286: 25505-25518.
PMID 21628462
Cleavage activation of human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12.
Hamilton BS, Whittaker GR.
J Biol Chem 2013; 288: 17399-17407.
PMID 23612974
Inhibition of kallikrein-related peptidases by the serine protease inhibitor of Kazal-type 6.
Kantyka T, Fischer J, Wu Z, Declercq W, Reiss K, Schroder JM, Meyer-Hoffert U.
Peptides 2011; 32: 1187-1192.
PMID 21439340
Angiogenesis stimulated by human kallikrein-related peptidase 12 acting via a platelet-derived growth factor B-dependent paracrine pathway.
Kryza T, Achard C, Parent C, Marchand-Adam S, Guillon-Munos A, Iochmann S, Korkmaz B, Respaud R, Courty Y, Heuze-Vourc'h N.
Faseb j 2014; 28: 740-751.
PMID 24225148
Pro-angiogenic effect of human kallikrein-related peptidase 12 (KLK12) in lung endothelial cells does not depend on kinin-mediated activation of B2 receptor.
Kryza T, Lalmanach G, Lavergne M, Lecaille F, Reverdiau P, Courty Y, Heuze-Vourc'h N.
Biol Chem 2013; 394: 385-391.
PMID 23152405
A survey of alternative transcripts of human tissue kallikrein genes.
Kurlender L, Borgono C, Michael IP, Obiezu C, Elliott MB, Yousef GM, Diamandis EP.
Biochim Biophys Acta 2005; 1755: 1-14.
PMID 15878240
Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness.
Lose F, Batra J, O'Mara T, Fahey P, Marquart L, Eeles RA, Easton DF, Al Olama AA, Kote-Jarai Z, Guy M, Muir K, Lophatananon A, Rahman AA, Neal DE, Hamdy FC, Donovan JL, Chambers S, Gardiner RA, Aitken JF, Yaxley J, Alexander K, Clements JA, Spurdle AB, Kedda MA.
Urol Oncol 2013; 31: 635-643.
PMID 21741862
Enzymatic properties of human kallikrein-related peptidase 12 (KLK12).
Memari N, Jiang W, Diamandis EP, Luo LY.
Biol Chem 2007; 388: 427-435.
PMID 17391064
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
Splice-site genetic polymorphism of the human kallikrein 12 (KLK12) gene correlates with no substantial expression of KLK12 protein having serine protease activity.
Shinmura K, Tao H, Yamada H, Kataoka H, Sanjar R, Wang J, Yoshimura K, Sugimura H.
Human mutation 2004; 24: 273-274.
PMID 15300858
Human kallikrein-related peptidase 12 (KLK12) splice variants expression in breast cancer and their clinical impact.
Talieri M, Devetzi M, Scorilas A, Pappa E, Tsapralis N, Missitzis I, Ardavanis A.
Tumour Biol 2012; 33: 1075-1084.
PMID 22351561
KLK12 is a novel serine protease and a new member of the human kallikrein gene family-differential expression in breast cancer.
Yousef GM, Magklara A, Diamandis EP.
Genomics 2000; 69: 331-341.
PMID 11056051
Clinical significance of human kallikrein 12 gene expression in gastric cancer.
Zhao EH, Shen ZY, Liu H, Jin X, Cao H.
World J Gastroenterol 2012; 18: 6597-6604.
PMID 23236234


This paper should be referenced as such :
Kontos CK, Scorilas A
KLK12 (kallikrein-related peptidase 12);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

External links

HGNC (Hugo)KLK12   6360
Entrez_Gene (NCBI)KLK12  43849  kallikrein related peptidase 12
AliasesKLK-L5; KLKL5
GeneCards (Weizmann)KLK12
Ensembl hg19 (Hinxton)ENSG00000186474 [Gene_View]  chr19:51532348-51538148 [Contig_View]  KLK12 [Vega]
Ensembl hg38 (Hinxton)ENSG00000186474 [Gene_View]  chr19:51532348-51538148 [Contig_View]  KLK12 [Vega]
ICGC DataPortalENSG00000186474
TCGA cBioPortalKLK12
AceView (NCBI)KLK12
Genatlas (Paris)KLK12
SOURCE (Princeton)KLK12
Genetics Home Reference (NIH)KLK12
Genomic and cartography
GoldenPath hg19 (UCSC)KLK12  -     chr19:51532348-51538148 -  19q13.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KLK12  -     19q13.33   [Description]    (hg38-Dec_2013)
EnsemblKLK12 - 19q13.33 [CytoView hg19]  KLK12 - 19q13.33 [CytoView hg38]
Mapping of homologs : NCBIKLK12 [Mapview hg19]  KLK12 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AY358524 BC035385 BC136341 BC143988 BC143990
RefSeq transcript (Entrez)NM_019598 NM_145894 NM_145895
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)KLK12
Cluster EST : UnigeneHs.411572 [ NCBI ]
CGAP (NCI)Hs.411572
Alternative Splicing GalleryENSG00000186474
Gene ExpressionKLK12 [ NCBI-GEO ]   KLK12 [ EBI - ARRAY_EXPRESS ]   KLK12 [ SEEK ]   KLK12 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK12 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)43849
GTEX Portal (Tissue expression)KLK12
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UKR0 (Uniprot)
NextProtQ9UKR0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UKR0
Splice isoforms : SwissVarQ9UKR0 (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_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)  
DMDM Disease mutations43849
Blocks (Seattle)KLK12
Human Protein AtlasENSG00000186474
Peptide AtlasQ9UKR0
IPIIPI00007724   IPI00220155   IPI00941336   IPI00395677   IPI00983268   IPI00985039   IPI00010516   
Protein Interaction databases
IntAct (EBI)Q9UKR0
Ontologies - Pathways
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  proteolysis  peptidase activity  serine-type peptidase activity  extracellular exosome  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  proteolysis  peptidase activity  serine-type peptidase activity  extracellular exosome  
NDEx NetworkKLK12
Atlas of Cancer Signalling NetworkKLK12
Wikipedia pathwaysKLK12
Orthology - Evolution
GeneTree (enSembl)ENSG00000186474
Phylogenetic Trees/Animal Genes : TreeFamKLK12
Homologs : HomoloGeneKLK12
Homology/Alignments : Family Browser (UCSC)KLK12
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK12 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK12
Exome Variant ServerKLK12
ExAC (Exome Aggregation Consortium)KLK12 (select the gene name)
Genetic variants : HAPMAP43849
Genomic Variants (DGV)KLK12 [DGVbeta]
DECIPHER (Syndromes)19:51532348-51538148  ENSG00000186474
CONAN: Copy Number AnalysisKLK12 
ICGC Data PortalKLK12 
TCGA Data PortalKLK12 
Broad Tumor PortalKLK12
OASIS PortalKLK12 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK12 
Mutations and Diseases : HGMDKLK12
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 KLK12
DgiDB (Drug Gene Interaction Database)KLK12
DoCM (Curated mutations)KLK12 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK12 (select a term)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry KLK12
NextProtQ9UKR0 [Medical]
Huge Navigator KLK12 [HugePedia]
snp3D : Map Gene to Disease43849
BioCentury BCIQKLK12
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD43849
Chemical/Pharm GKB GenePA30149
Clinical trialKLK12
canSAR (ICR)KLK12 (select the gene name)
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Oct 12 17:29:50 CEST 2016

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