KLKs: A Family of Multifaceted Proteases

Kallikrein-related peptidases (KLKs), a family of fifteen homologous serine proteases (KLK1-KLK15), exhibit critical roles in diverse physiological and pathological processes. Notable KLKs, including KLK3, KLK5, KLK6, KLK10, and KLK14, display key effects in regulating cancer genesis, growth, migration, invasion, and chemoresistance, influencing intricate molecular networks associated with cancer cell survival and dissemination. The functional relevance of KLKs in cancer progression makes them important biomarkers and therapeutic targets in various cancers. In translational medicine, KLK1, KLK2, KLK3, KLK5, KLK7, KLK14, and KLKB1 have been utilized for the design of KLK-targeted therapies, holding promise for treating cancers, nervous system diseases, dermatological disorders, and other medical fields. Sino Biological is committed to advance KLK-targeted drug development, providing a comprehensive selection of recombinant KLK proteins and corresponding antibodies, which plays a crucial role in KLK-related research, as demonstrated in studies utilizing these products for isoform mapping, ELISA measurements, and identifying highly expressed kallikreins in specific carcinomas.

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Physiological and Pathological Roles

KLKs are involved in various physiological processes, such as skin desquamation, semen liquefaction, tooth enamel formation, immune response regulation, and neural development. On the other hand, dysfunction in KLK regulation is implicated in numerous pathophysiological processes ranging from prostate and ovarian cancers to lung disease, hypertension, and diabetes to cardiovascular disease.(1–3) Some of the most studied KLKs in cancer are KLK3 (PSA) for prostate cancer, KLK6 and KLK10 for ovarian cancer, and KLK5 and KLK14 for breast cancer. (4,5) In different specific cancer types, the expression of each KLK is differentially regulated by tumor-promoting or tumor-suppressing effects.(1,6,7) The excessive molecular network of KLKs includes cross-talk with uPAs, PARs, Kinin, TGF-b, and MMPs, collectively promoting survival, proliferation, and dissemination of cancer cells.(8,9)

Bench to Bedside

KLKs, such as KLK1, KLK2, KLK3, KLK5, KLK7, KLK14, and KLKB1, hold promise in various medical fields (Table 1). KLK1, for instance, shows potential in treating nervous system diseases, autoimmune conditions, stroke, and diabetic kidney disease, emphasizing its relevance in neurology and endocrinology. KLK2 and KLK3 play significant roles in different cancer types, including castration-resistant and metastatic prostate cancers, pancreatic cancer, as well as atopic dermatitis. Dermatological disorders like atopic dermatitis, psoriasis, and Netherton syndrome are associated with KLK5 and KLK7, offering avenues for innovative therapies. KLK14's involvement in Netherton syndrome, prostate cancer, and atopic dermatitis suggests its versatility as a therapeutic target. Additionally, KLKB1's connections to retinopathy, diabetes, macular degeneration, allergies, and coagulopathies underscore its importance in ophthalmology, endocrinology, and hematology.

Application in Research

Sino Biological’s products play a crucial role in KLK-related research, as demonstrated by frequently cited in well-reputed journals. These products support studies such as isozyme mapping, ELISA measurements, and identification of highly expressed Kallikreins in specific carcinomas. Fu et al. used anti-KLK3 rabbit monoclonal antibody (Sino Biological) as an IgG control isotype in the isoform mapping and interactome studies of endogenous TMPRSSS2-ERG fusion protein in VCaP prostate cancer cells by orthogonal immunoprecipitation-mass spectrometry assays, supporting the development of more accurate prostate cancer diagnostics.(10) Egidi et al. used human KLK11 and KLK13 ELISA kits (Sino Biological) to measure KLKs (hK11 and hK13) in preoperative and postoperative serum samples from prostate cancer patients, and found that there was a significant decrease in KLK in postoperative serum.(11) In another study, Hashemipour et al. identified that human tissue kallikreins are highly expressed in pleomorphic adenomas and mucoepidermoid carcinomas, where lysate from 293T cells transfected with KLK10 and KLK11 (Sino Biological) were served as controls. (12)

Sino Biological’s Recombinant KLKs Validated by MMS >>

References

1. Filippou, P. S., Karagiannis, G. S., Musrap, N. & Diamandis, E. P. Kallikrein-related peptidases (KLKs) and the hallmarks of cancer. Critical Reviews in Clinical Laboratory Sciences vol. 53 277–291 Preprint at https://doi.org/10.3109/10408363.2016.1154643 (2016).

2. Kalinska, M., Meyer-Hoffert, U., Kantyka, T. & Potempa, J. Kallikreins - The melting pot of activity and function. Biochimie vol. 122 270–282 Preprint at https://doi.org/10.1016/j.biochi.2015.09.023 (2016).

3. Bouzid, H. et al. Kallikrein-Related Peptidase 6 (KLK6) as a Contributor toward an Aggressive Cancer Cell Phenotype: A Potential Role in Colon Cancer Peritoneal Metastasis. Biomolecules 12, (2022).

4. Figueroa, C. D., Molina, L., Bhoola, K. D. & Ehrenfeld, P. Overview of tissue kallikrein and kallikrein-related peptidases in breast cancer. Biol Chem 399, 937–957 (2018).

5. Peng, Q. et al. Biomarker implication of kallikrein-related peptidases as prognostic tissue substrates of poor survival in colorectal cancer. Cancer Cell Int 20, (2020).

6. Gong, W. et al. Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer. J Ovarian Res 13, (2020).

7. Chen, E. et al. Analysis of expression and prognosis of KLK7 in ovarian cancer. Open Medicine (Poland) 15, 932–939 (2020).

8. Hsieh, H. L., Wang, H. H., Wu, W. Bin, Chu, P. J. & Yang, C. M. Transforming growth factor-β1 induces matrix metalloproteinase-9 and cell migration in astrocytes: Roles of ROS-dependent ERK- and JNK-NF-κB pathways. J Neuroinflammation 7, (2010).

9. Gomes, L. R., Terra, L. F., Wailemann, R. A. M., Labriola, L. & Sogayar, M. C. TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells. BMC Cancer 12, (2012).

10. Fu, Z. et al. Mapping isoform abundance and interactome of the endogenous TMPRSS2-ERG fusion protein by orthogonal immunoprecipitation-mass spectrometry assays. Molecular and Cellular Proteomics 20, (2021).

11. Egidi, M. G. et al. Circulating microRNAs and Kallikreins before and after radical prostatectomy: Are they really prostate cancer markers? Biomed Res Int 2013, (2013).

12. Hashemipour, M. A., Fatah, F. S., Ashraf, M. J. & Tahmasebi, M. Expression of Human Kallikreins 4, 8, 10, 11 and 13 in Pleomorphic Adenomas and Mucoepidermoid Carcinomas. Iran J Pathol 11, 334–344 (2016).