Genomes and Genes
Summary: Proteolytic enzymes from the serine endopeptidase family found in normal blood and urine. Specifically, Kallikreins are potent vasodilators and hypotensives and increase vascular permeability and affect smooth muscle. They act as infertility agents in men. Three forms are recognized, PLASMA KALLIKREIN (EC 18.104.22.168), TISSUE KALLIKREIN (EC 22.214.171.124), and PROSTATE-SPECIFIC ANTIGEN (EC 126.96.36.199).
- Dorn J, Bayani J, Yousef G, Yang F, Magdolen V, Kiechle M, et al. Clinical utility of kallikrein-related peptidases (KLK) in urogenital malignancies. Thromb Haemost. 2013;110:408-22 pubmed publisher..Evidently, depending on the type of cancer or cancer stage, individual KLKs may show characteristics of a Janus-faced behaviour, by either expanding or inhibiting cancer progression and metastasis. ..
- Jin Y, Qu S, Tesikova M, Wang L, Kristian A, Mælandsmo G, et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc Natl Acad Sci U S A. 2013;110:E2572-81 pubmed publisher..These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy. ..
- Petraki C, Dubinski W, Scorilas A, Saleh C, Pasic M, Komborozos V, et al. Evaluation and prognostic significance of human tissue kallikrein-related peptidase 6 (KLK6) in colorectal cancer. Pathol Res Pract. 2012;208:104-8 pubmed publisher..041). Kaplan-Meier survival curves showed that KLK6-positive patients have statistically significant lower disease-free and overall survival. In conclusion, KLK6 immunostaining is an independent prognostic marker in patients with CRC. ..
- Hu Y, Hu J, Smith C, Bartlett J, Simmer J. Kallikrein-related peptidase 4, matrix metalloproteinase 20, and the maturation of murine and porcine enamel. Eur J Oral Sci. 2011;119 Suppl 1:217-25 pubmed publisher..We conclude that enamel breaks in the deep enamel of Klk4 null mice because of decreasing enamel maturation with depth, and at the DEJ in Mmp20 null mice because of hypomineralization at the DEJ...
- Pépin D, Shao Z, Huppé G, Wakefield A, Chu C, Sharif Z, et al. Kallikreins 5, 6 and 10 differentially alter pathophysiology and overall survival in an ovarian cancer xenograft model. PLoS ONE. 2011;6:e26075 pubmed publisherHuman tissue kallikreins (KLKs) are members of a multigene family of serine proteases aberrantly expressed in many cancer types...
- Kim J, Kim J, Yoon H, Kang M, Kim J, Lee Y, et al. Upregulation and secretion of kallikrein-related peptidase 6 (KLK6) in gastric cancer. Tumour Biol. 2012;33:731-8 pubmed publisher..This study shows that KLK6 is significantly upregulated and secreted in gastric cancer tissues and sera, suggesting that KLK6 might be used as a potential biomarker and therapeutic target for gastric cancer. ..
- de Veer S, Swedberg J, Parker E, Harris J. Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14. Biol Chem. 2012;393:331-41 pubmed publisher..Collectively, these findings highlight the importance of binding site cooperativity in protease substrate recognition, which has implications for discovery of optimal substrates and engineering highly effective protease inhibitors. ..
- Seiz L, Dorn J, Kotzsch M, Walch A, Grebenchtchikov N, Gkazepis A, et al. Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients. Biol Chem. 2012;393:391-401 pubmed publisher..low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer. ..
- Sotiropoulou G, Pampalakis G. Targeting the kallikrein-related peptidases for drug development. Trends Pharmacol Sci. 2012;33:623-34 pubmed publisher..Here, we review current approaches for the design and testing of KLK-based therapeutics. ..
- Verweij N, Mahmud H, Mateo Leach I, de Boer R, Brouwers F, Yu H, et al. Genome-wide association study on plasma levels of midregional-proadrenomedullin and C-terminal-pro-endothelin-1. Hypertension. 2013;61:602-8 pubmed publisher..The discovery of genetic variants in the kallikrein-kinin system and in the genes encoding pre-pro-ET-1 and pre-pro-ADM provides novel insights into the (co-)regulation of these vasoactive peptides in the vascular system. ..
- Ruckert F, Hennig M, Petraki C, Wehrum D, Distler M, Denz A, et al. Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma. Br J Cancer. 2008;99:1484-92 pubmed publisherb>Kallikreins play an important role in tumour microenvironment and as cancer biomarkers in different cancer entities. Previous studies suggested an upregulation of KLK10 and KLK6 in pancreatic ductal adenocarcinoma (PDAC)...
- Blaber S, Yoon H, Scarisbrick I, Juliano M, Blaber M. The autolytic regulation of human kallikrein-related peptidase 6. Biochemistry. 2007;46:5209-17 pubmed..The results thus show that the primary autolytic regulatory mechanism of KLK6 is negative feedback inhibition, and activation is likely achieved through the action of a separate protease. ..
- Wilkinson R, Woods K, D Rozario R, Prue R, Vari F, Hardy M, et al. Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients. Cancer Immunol Immunother. 2012;61:169-179 pubmed publisher..These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy. ..
- Shaw J, Diamandis E. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem. 2007;53:1423-32 pubmedb>Kallikreins (KLKs) are a group of 15 secreted serine proteases. Some KLKs are established or candidate cancer biomarkers, but for most the physiological function is unknown...
- Yousef G. microRNAs: a new frontier in kallikrein research. Biol Chem. 2008;389:689-94 pubmed publisher..Many kallikreins have been reported as potential tumor markers...
- White N, Mathews M, Yousef G, Prizada A, Popadiuk C, Doré J. KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma. Br J Cancer. 2009;101:1107-13 pubmed publisher..In all, this study shows KLK6 and KLK13 as potential biomarkers and may be therapeutic targets for treatment of ovarian cancer. ..
- Ohler A, Debela M, Wagner S, Magdolen V, Becker Pauly C. Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol Chem. 2010;391:455-60 pubmed publisher..In summary, we demonstrate a specific interaction between meprin metalloproteases and kallikrein-related peptidases, revealing possible interactions within the proteolytic web. ..
- Swedberg J, de Veer S, Harris J. Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia. Biol Chem. 2010;391:357-74 pubmed publisherThe kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure...
- Beaufort N, Plaza K, Utzschneider D, Schwarz A, Burkhart J, Creutzburg S, et al. Interdependence of kallikrein-related peptidases in proteolytic networks. Biol Chem. 2010;391:581-7 pubmed publisher..Our observations provide new insights into the regulation of these important tumor-associated proteases. ..
- Meyer Hoffert U. Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases. Arch Immunol Ther Exp (Warsz). 2009;57:345-54 pubmed publisher..Endogenous and exogenous proteases such as kallikreins, matriptase, caspases, cathepsins, and proteases derived from microorganisms are important in the desquamation ..
- Ramani V, Haun R. Expression of kallikrein 7 diminishes pancreatic cancer cell adhesion to vitronectin and enhances urokinase-type plasminogen activator receptor shedding. Pancreas. 2008;37:399-404 pubmed publisher..Kallikrein 7 expression, therefore, may play an important role in the dissemination of tumor cells through the production of soluble uPAR in pancreatic cancer and perhaps other human malignancies. ..
- Henkhaus R, Gerner E, Ignatenko N. Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells. Biol Chem. 2008;389:757-64 pubmed publisher..These data support the oncogenic role of KLK6 in colorectal cancer. ..
- Lundwall A, Brattsand M. Kallikrein-related peptidases. Cell Mol Life Sci. 2008;65:2019-38 pubmed publisher..In this review on kallikrein-related peptidases, the focus is on their evolution, their role in skin homeostasis and semen liquefaction, and their utility as cancer biomarkers. ..
- Sotiropoulou G, Pampalakis G, Diamandis E. Functional roles of human kallikrein-related peptidases. J Biol Chem. 2009;284:32989-94 pubmed publisher..In addition, KLKs have emerged as versatile signaling molecules. In summary, KLKs represent attractive biomarkers for clinical applications and potential therapeutic targets for common human pathologies. ..
- Debela M, Hess P, Magdolen V, Schechter N, Steiner T, Huber R, et al. Chymotryptic specificity determinants in the 1.0 A structure of the zinc-inhibited human tissue kallikrein 7. Proc Natl Acad Sci U S A. 2007;104:16086-91 pubmed..Similar to several other kallikreins, the enzyme activity is inhibited by Zn(2+) and Cu(2+) at low micromolar concentrations...
- Lai J, Myers S, Lawrence M, Odorico D, Clements J. Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer. Mol Cancer Res. 2009;7:129-41 pubmed publisher..pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at -2419 bp. ..
- Yoon H, Laxmikanthan G, Lee J, Blaber S, Rodriguez A, Kogot J, et al. Activation profiles and regulatory cascades of the human kallikrein-related peptidases. J Biol Chem. 2007;282:31852-64 pubmed..One such tissue-specific cascade is proposed for the central nervous system. ..
- Goettig P, Magdolen V, Brandstetter H. Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs). Biochimie. 2010;92:1546-67 pubmed publisher..Thus, down regulation of excessive KLK activity in cancer and in skin diseases by small inhibitor compounds may represent attractive therapeutical approaches. ..
- Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell. 2007;18:3607-19 pubmed..All LEKTI fragments, except D1, showed specific and differential inhibition of human kallikreins 5, 7, and 14. The strongest inhibition was observed with D8-D11, toward KLK5...
- Fortugno P, Bresciani A, Paolini C, Pazzagli C, El Hachem M, D Alessio M, et al. Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. J Invest Dermatol. 2011;131:2223-32 pubmed publisher..We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the ..
- Klein R, Hallden C, Cronin A, Ploner A, Wiklund F, Bjartell A, et al. Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer. Cancer Prev Res (Phila). 2010;3:611-9 pubmed publisher..874 versus 0.866), providing proof in principle to clinical application for our findings. ..
- Debela M, Goettig P, Magdolen V, Huber R, Schechter N, Bode W. Structural basis of the zinc inhibition of human tissue kallikrein 5. J Mol Biol. 2007;373:1017-31 pubmed..The His96-99-57 triad is thus suggested to be responsible for the Zn2+-mediated inhibition of hK5 catalysis. ..
- Lawrence M, Veveris Lowe T, Whitbread A, Nicol D, Clements J. Epithelial-mesenchymal transition in prostate cancer and the potential role of kallikrein serine proteases. Cells Tissues Organs. 2007;185:111-5 pubmed
- Oikonomopoulou K, Batruch I, Smith C, Soosaipillai A, Diamandis E, Hollenberg M. Functional proteomics of kallikrein-related peptidases in ovarian cancer ascites fluid. Biol Chem. 2010;391:381-90 pubmed publisher..g., alpha2-macroglobulin, alpha1-antitrypsin). Our data suggest that the enzymatic activity of ovarian cancer-released KLKs that are detected by regular immunoassays is low in vivo and very likely regulated by proteinase inhibitors. ..
- Vickers A, Cronin A, Roobol M, Savage C, Peltola M, Pettersson K, et al. A four-kallikrein panel predicts prostate cancer in men with recent screening: data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam. Clin Cancer Res. 2010;16:3232-9 pubmed publisher..A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA...
- Talieri M, Li L, Zheng Y, Alexopoulou D, Soosaipillai A, Scorilas A, et al. The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer. Br J Cancer. 2009;100:1659-65 pubmed publisher..86 beyond the clinical factors at year 1, showing that it can increase the accuracy of prediction of overall survival beyond the traditional clinical information, particularly the short-term (1 year) survival after surgery. ..
- Yoon H, Blaber S, Debela M, Goettig P, Scarisbrick I, Blaber M. A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15. Biol Chem. 2009;390:373-7 pubmed publisher..Conversely, KLK9 and 10, once activated, are unlikely to participate in further pro-KLK activation pathways, although similar to KLK1 they may activate other bioactive peptides. ..
- Horii Y, Yamasaki N, Miyakawa T, Shiosaka S. Increased anxiety-like behavior in neuropsin (kallikrein-related peptidase 8) gene-deficient mice. Behav Neurosci. 2008;122:498-504 pubmed publisher..Here, the authors found increased anxiety in neuropsin-deficient mice, suggesting the involvement of this protease in emotional responses. ..
- Emami N, Deperthes D, Malm J, Diamandis E. Major role of human KLK14 in seminal clot liquefaction. J Biol Chem. 2008;283:19561-9 pubmed publisher..Semenogelins were also able to reverse KLK14 inhibition by Zn2+, providing a novel regulatory mechanism for KLK14 activity. Our results show that KLK14 exerts a significant and dose-dependent effect in the process of semen liquefaction. ..
- Emami N, Diamandis E. Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade. Possible function in seminal plasma and skin. J Biol Chem. 2008;283:3031-41 pubmed..We are proposing a putative cascade model, operating through multiple KLKs. Identification of novel members of such proteolytic cascades will aid in further defining mechanisms involved in seminal/skin homeostasis. ..
- Kishibe M, Bando Y, Terayama R, Namikawa K, Takahashi H, Hashimoto Y, et al. Kallikrein 8 is involved in skin desquamation in cooperation with other kallikreins. J Biol Chem. 2007;282:5834-41 pubmed..We propose that in psoriatic lesion, KLK8 modulates hyperproliferation and prevents excessive hyperkeratosis by shedding the corneocytes. ..
- Yoshida S. Klk8, a multifunctional protease in the brain and skin: analysis of knockout mice. Biol Chem. 2010;391:375-80 pubmed publisher..Klk8 might be involved in desquamation through the degradation of adhesive molecules that connect layers of the epidermis. Klk8 might thus be involved in tissue development and rearrangement. ..
- Wright J, Hart T, Hart P, Simmons D, Suggs C, Daley B, et al. Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4. Cells Tissues Organs. 2009;189:224-9 pubmed publisher..Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions. ..
- Avgeris M, Stravodimos K, Scorilas A. Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: quantitative expression analysis and evaluation of its clinical significance. Prostate. 2011;71:1780-9 pubmed publisher..KLK4 quantification serves as an independent biomarker for the discrimination between the malignant and the benign nature of prostate tumors. ..
- Vickers A, Cronin A, Roobol M, Savage C, Peltola M, Pettersson K, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010;28:2493-8 pubmed publisher..We have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA...
- Swedberg J, Nigon L, Reid J, de Veer S, Walpole C, Stephens C, et al. Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chem Biol. 2009;16:633-43 pubmed publisher..The re-engineered inhibitor was designed using a combination of molecular modeling and sparse matrix substrate screening. ..
- Mize G, Wang W, Takayama T. Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Mol Cancer Res. 2008;6:1043-51 pubmed publisher..been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth...
- Memari N, Jiang W, Diamandis E, Luo L. Enzymatic properties of human kallikrein-related peptidase 12 (KLK12). Biol Chem. 2007;388:427-35 pubmed..Furthermore, we demonstrate that KLK12 is able to activate KLK11 zymogen in vitro. Our results indicate that KLK12 may participate in enzymatic cascades involving other kallikreins.