| 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. |
| 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. |
| | |
| 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 |
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| 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 |
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| 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 |
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| 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, |
| Clin Chem. 2002; 48: 1241-1250. |
| PMID 12142380 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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, |
| Tumour Biol. 2004; 25: 149-156. |
| PMID 15361712 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Distribution of 15 human kallikreins in tissues and biological fluids. |
| Shaw JL, Diamandis EP. |
| Clin Chem. 2007; 53: 1423-32. |
| PMID 17573418 |
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| 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 |
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| 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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