Download Gene Section KLK5 (Kallikrein-related peptidase 5) Atlas of Genetics and Cytogenetics

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KLK5 (Kallikrein-related peptidase 5)
George 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)
Published in Atlas Database: June 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/KLK5ID41085ch19q13.html
DOI: 10.4267/2042/44470
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: EC 3.4.21; HSCTE; KLK-L2; KLKL2;
SCTE
HGNC (Hugo): KLK5
Location: 19q13.41
Local order: Telomere to centromere.
DNA/RNA
Expression
Description
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.
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.
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 "cystatinlike domain 3" from low molecular weight kininogen,
and fibrinopeptide B and peptide beta15-42 from the B
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 Nlinked glycosylation sites. The position of the catalytic
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
357
KLK5 (Kallikrein-related peptidase 5)
Yousef GM, Diamandis EP
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.
overexpressed in node-positive patients with ERnegative 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.
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.
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.
Mutations
Note
No germinal or somatic mutations are identified to be
associated with cancer so far.
Implicated in
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,
especially 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.
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.
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.
Breast cancer
Disease
Higher concentrations of KLK5 were found
serum of 49% of patients with breast cancer.
splice variant 2 is downregulated in breast
compared to normal.
Prognosis
The KLK5 mRNA transcript was found to
indicator of unfavorable prognosis, being
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
Urinary bladder carcinoma
in the
KLK5
cancer
Disease
None identified.
Prognosis
Increased expression of KLK5 was frequently observed
in invasive tumors (pT2-pT4) compared with
superficial tumors (pTa, pT1).
be an
358
KLK5 (Kallikrein-related peptidase 5)
Yousef GM, Diamandis EP
Yousef GM, Polymeris ME, Yacoub GM, Scorilas A,
Soosaipillai A, Popalis C, Fracchioli S, Katsaros D, Diamandis
EP. Parallel overexpression of seven kallikrein genes in
ovarian cancer. Cancer Res. 2003 May 1;63(9):2223-7
Cytogenetics
Copy number gain was observed in transitional cell
carcinoma.
Hybrid/Mutated gene
None identified.
Kurlender L, Yousef GM, Memari N, Robb JD, Michael IP,
Borgoño C, Katsaros D, Stephan C, Jung K, Diamandis EP.
Differential expression of a human kallikrein 5 (KLK5) splice
variant in ovarian and prostate cancer. Tumour Biol. 2004 MayJun;25(3):149-56
Breakpoints
Note
None identified.
Yousef GM, White NM, Kurlender L, Michael I, Memari N,
Robb JD, Katsaros D, Stephan C, Jung K, Diamandis EP. The
kallikrein gene 5 splice variant 2 is a new biomarker for breast
and ovarian cancer. Tumour Biol. 2004 Sep-Dec;25(5-6):221-7
References
Yousef GM, Yacoub GM, Polymeris ME, Popalis C,
Soosaipillai A, Diamandis EP. Kallikrein gene downregulation
in breast cancer. Br J Cancer. 2004 Jan 12;90(1):167-72
Kim H, Scorilas A, Katsaros D, Yousef GM, Massobrio M,
Fracchioli S, Piccinno R, Gordini G, Diamandis EP. Human
kallikrein gene 5 (KLK5) expression is an indicator of poor
prognosis in ovarian cancer. Br J Cancer. 2001 Mar
2;84(5):643-50
Michael IP, Sotiropoulou G, Pampalakis G, Magklara A, Ghosh
M, Wasney G, Diamandis EP. Biochemical and enzymatic
characterization of human kallikrein 5 (hK5), a novel serine
protease potentially involved in cancer progression. J Biol
Chem. 2005 Apr 15;280(15):14628-35
Yousef GM, Obiezu CV, Jung K, Stephan C, Scorilas A,
Diamandis EP. Differential expression of Kallikrein gene 5 in
cancerous and normal testicular tissues. Urology. 2002
Oct;60(4):714-8
Planque C, de Monte M, Guyetant S, Rollin J, Desmazes C,
Panel V, Lemarié E, Courty Y. KLK5 and KLK7, two members
of the human tissue kallikrein family, are differentially
expressed in lung cancer. Biochem Biophys Res Commun.
2005 Apr 22;329(4):1260-6
Yousef GM, Scorilas A, Chang A, Rendl L, Diamandis M, Jung
K, Diamandis EP. Down-regulation of the human kallikrein
gene 5 (KLK5) in prostate cancer tissues. Prostate. 2002 May
1;51(2):126-32
Prezas P, Arlt MJ, Viktorov P, Soosaipillai A, Holzscheiter L,
Schmitt M, Talieri M, Diamandis EP, Krüger A, Magdolen V.
Overexpression of the human tissue kallikrein genes KLK4, 5,
6, and 7 increases the malignant phenotype of ovarian cancer
cells. Biol Chem. 2006 Jun;387(6):807-11
Yousef GM, Scorilas A, Kyriakopoulou LG, Rendl L, Diamandis
M, Ponzone R, Biglia N, Giai M, Roagna R, Sismondi P,
Diamandis EP. Human kallikrein gene 5 (KLK5) expression by
quantitative PCR: an independent indicator of poor prognosis
in breast cancer. Clin Chem. 2002 Aug;48(8):1241-50
Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in
tissues and biological fluids. Clin Chem. 2007 Aug;53(8):142332
Dong Y, Kaushal A, Brattsand M, Nicklin J, Clements JA.
Differential splicing of KLK5 and KLK7 in epithelial ovarian
cancer produces novel variants with potential as cancer
biomarkers. Clin Cancer Res. 2003 May;9(5):1710-20
Shinoda Y, Kozaki K, Imoto I, Obara W, Tsuda H, Mizutani Y,
Shuin T, Fujioka T, Miki T, Inazawa J. Association of KLK5
overexpression with invasiveness of urinary bladder carcinoma
cells. Cancer Sci. 2007 Jul;98(7):1078-86
Yousef GM, Kapadia C, Polymeris ME, Borgono C, Hutchinson
S, Wasney GA, Soosaipillai A, Diamandis EP. The human
kallikrein protein 5 (hK5) is enzymatically active, glycosylated
and forms complexes with two protease inhibitors in ovarian
cancer fluids. Biochim Biophys Acta. 2003 Jul 28;1628(2):8896
Planque C, Li L, Zheng Y, Soosaipillai A, Reckamp K, Chia D,
Diamandis EP, Goodglick L. A multiparametric serum kallikrein
panel for diagnosis of non-small cell lung carcinoma. Clin
Cancer Res. 2008 Mar 1;14(5):1355-62
Yousef GM, Polymeris ME, Grass L, Soosaipillai A, Chan PC,
Scorilas A, Borgoño C, Harbeck N, Schmalfeldt B, Dorn J,
Schmitt M, Diamandis EP. Human kallikrein 5: a potential novel
serum biomarker for breast and ovarian cancer. Cancer Res.
2003 Jul 15;63(14):3958-65
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5)
This article should be referenced as such:
Yousef GM, Diamandis EP. KLK5 (Kallikrein-related peptidase
5). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5):357359.
359