Home Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor
Article
Licensed
Unlicensed Requires Authentication

Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor

  • Marion Lavergne ORCID logo EMAIL logo , Audrey Guillon-Munos , Woodys Lenga Ma Bonda , Sylvie Attucci , Thomas Kryza , Aurélia Barascu , Thierry Moreau , Agnès Petit-Courty , Damien Sizaret , Yves Courty , Sophie Iochmann and Pascale Reverdiau EMAIL logo
Published/Copyright: May 12, 2021
Biological Chemistry
From the journal Biological Chemistry Volume 402 Issue 10

Abstract

The protease activities are tightly regulated by inhibitors and dysregulation contribute to pathological processes such as cancer and inflammatory disorders. Tissue factor pathway inhibitor 2 (TFPI-2) is a serine proteases inhibitor, that mainly inhibits plasmin. This protease activated matrix metalloproteases (MMPs) and degraded extracellular matrix. Other serine proteases are implicated in these mechanisms like kallikreins (KLKs). In this study, we identified for the first time that TFPI-2 is a potent inhibitor of KLK5 and 12. Computer modeling showed that the first Kunitz domain of TFPI-2 could interact with residues of KLK12 near the catalytic triad. Furthermore, like plasmin, KLK12 was able to activate proMMP-1 and -3, with no effect on proMMP-9. Thus, the inhibition of KLK12 by TFPI-2 greatly reduced the cascade activation of these MMPs and the cleavage of cysteine-rich 61, a matrix signaling protein. Moreover, when TFPI-2 bound to extracellular matrix, its classical localisation, the KLK12 inhibition was retained. Finally, TFPI-2 was downregulated in human non-small-cell lung tumour tissue as compared with non-affected lung tissue. These data suggest that TFPI-2 is a potent inhibitor of KLK12 and could regulate matrix remodeling and cancer progression mediated by KLK12.

Keywords: CCN; extracellular matrix; lung cancer; matrix metalloproteinase; protease inhibitor; serine protease
Corresponding authors: Marion Lavergne, Université de Tours, F-37032 Tours, France; and INSERM, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100, 10 boulevard Tonnellé, F-37000 Tours, France, E-mail: ; and Pascale Reverdiau, Université de Tours, F-37032 Tours, France; INSERM, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100, 10 boulevard Tonnellé, F-37000 Tours, France; and Institut Universitaire de Technologie, F-37082 Tours, France, E-mail:

Funding source: Ligue Contre le Cancer

Acknowledgements

We are grateful to Alexandre Lebrun for excellent technical assistance. We particularly thank Laura Smales for editing the English text. Studies conducted by our team were supported by the “Ligue Contre le Cancer” and we especially thank the departmental committees of the French departments Indre et Loire, Morbihan, Maine et Loire, Deux-Sèvres, Indre, and Cher.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Bieth, J.G. (1984). In vivo significance of kinetic constants of protein proteinase inhibitors. Biochem. Med. 32: 387–397, https://doi.org/10.1016/0006-2944(84)90046-2.Search in Google Scholar

Borgoño, C.A. and Diamandis, E.P. (2004). The emerging roles of human tissue kallikreins in cancer. Nat. Rev. Cancer 4: 876–890, https://doi.org/10.1038/nrc1474.Search in Google Scholar PubMed

Chand, H.S., Foster, D.C., and Kisiel, W. (2005). Structure, function and biology of tissue factor pathway inhibitor-2. Thromb. Haemost. 94: 1122–1130, https://doi.org/10.1160/th05-07-0509.Search in Google Scholar PubMed

Chand, H.S., Schmidt, A.E., Bajaj, S.P., and Kisiel, W. (2004). Structure-function analysis of the reactive site in the first Kunitz-type domain of human tissue factor pathway inhibitor-2. J. Biol. Chem. 279: 17500–17507, https://doi.org/10.1074/jbc.m400802200.Search in Google Scholar

Deryugina, E.I. and Quigley, J.P. (2012). Cell surface remodeling by plasmin: a new function for an old enzyme. J. Biomed. Biotechnol. 2012: 564259, https://doi.org/10.1155/2012/564259.Search in Google Scholar PubMed PubMed Central

de Souza, L.R., M Melo, P., Paschoalin, T., Carmona, A.K., Kondo, M., Hirata, I.Y., Blaber, M., Tersariol, I., Takatsuka, J., Juliano, M.A., et al.. (2013). Human tissue kallikreins 3 and 5 can act as plasminogen activator releasing active plasmin. Biochem. Biophys. Res. Commun. 433: 333–337, https://doi.org/10.1016/j.bbrc.2013.03.001.Search in Google Scholar PubMed

Egeblad, M. and Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2: 161–174, https://doi.org/10.1038/nrc745.Search in Google Scholar PubMed

Eissa, A. and Diamandis, E.P. (2008). Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions. Biol. Chem. 389: 669–680, https://doi.org/10.1515/bc.2008.079.Search in Google Scholar

Furio, L., Pampalakis, G., Michael, I.P., Nagy, A., Sotiropoulou, G., and Hovnanian, A. (2015). KLK5 inactivation reverses cutaneous hallmarks of Netherton syndrome. PLoS Genet. 11: e1005389. https://doi.org/10.1371/journal.pgen.1005389.Search in Google Scholar PubMed PubMed Central

Gaud, G., Iochmann, S., Guillon-Munos, A., Brillet, B., Petiot, S., Seigneuret, F., Touzé, A., Heuzé-Vourc h, N., Courty, Y., Lerondel, S., et al.. (2011). TFPI-2 silencing increases tumour progression and promotes metalloproteinase 1 and 3 induction through tumour-stromal cell interactions. J. Cell Mol. Med. 15: 196–208, https://doi.org/10.1111/j.1582-4934.2009.00989.x.Search in Google Scholar PubMed PubMed Central

Goettig, P., Magdolen, V., and Brandstetter, H. (2010). Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs). Biochimie 92: 1546–1567, https://doi.org/10.1016/j.biochi.2010.06.022.Search in Google Scholar

Gong, W., Liu, Y., Preis, S., Geng, X., Petit-Courty, A., Kiechle, M., Muckenhuber, A., Dreyer, T., Dorn, J., Courty, Y., et al.. (2020). Prognostic value of kallikrein-related peptidase 12 (KLK12). mRNA expression in triple-negative breast cancer patients. Mol. Med. 26: 19, https://doi.org/10.1186/s10020-020-0145-7.Search in Google Scholar

Gueugnon, F., Barascu, A., Mavridis, K., Petit-Courty, A., Marchand-Adam, S., Gissot, V., Scorilas, A., Guyetant, S., and Courty, Y. (2015). Kallikrein-related peptidase 13: an independent indicator of favorable prognosis for patients with nonsmall cell lung cancer. Tumour Biol 36: 4979–4986, https://doi.org/10.1007/s13277-015-3148-1.Search in Google Scholar

Guillon-Munos, A., Oikonomopoulou, K., Michel, N., Smith, C.R., Petit-Courty, A., Canepa, S., Reverdiau, P., Heuzé-Vourc h, N., Diamandis, E.P., and Courty, Y. (2011). Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors. J. Biol. Chem. 286: 25505–25518, https://doi.org/10.1074/jbc.m110.213231.Search in Google Scholar

Guo, H., Lin, Y., Zhang, H., Liu, J., Zhang, N., Li, Y., Kong, D., Tang, Q., and Ma, D. (2007). Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells. BMC Mol. Biol. 8: 110, https://doi.org/10.1186/1471-2199-8-110.Search in Google Scholar

Hibi, K., Goto, T., Kitamura, Y.H., Yokomizo, K., Sakuraba, K., Shirahata, A., Mizukami, H., Saito, M., Ishibashi, K., Kigawa, G., et al. (2010). Methylation of TFPI2 gene is frequently detected in advanced well-differentiated colorectal cancer. Anticancer Res. 30: 1205–1207.Search in Google Scholar

Hubé, F., Reverdiau, P., Iochmann, S., and Gruel, Y. (2003). Computer model of the interaction of human TFPI-2 Kunitz-type serine protease inhibitor with human plasmin. Thromb. Res. 111: 197–198, https://doi.org/10.1016/j.thromres.2003.09.021.Search in Google Scholar

Iino, M., Foster, D.C., and Kisiel, W. (1998). Quantification and characterization of human endothelial cell-derived tissue factor pathway inhibitor-2. Arterioscler. Thromb. Vasc. Biol. 18: 40–46, https://doi.org/10.1161/01.atv.18.1.40.Search in Google Scholar

Iochmann, S., Bléchet, C., Chabot, V., Saulnier, A., Amini, A., Gaud, G., Gruel, Y., and Reverdiau, P. (2009). Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion. Clin. Exp. Metastasis 26: 457–467, https://doi.org/10.1007/s10585-009-9245-z.Search in Google Scholar

Izumi, H., Takahashi, C., Oh, J., and Noda, M. (2000). Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogenes. FEBS Lett. 481: 31–36, https://doi.org/10.1016/s0014-5793(00)01902-5.Search in Google Scholar

Jun, J.I. and Lau, L.F. (2011). Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat. Rev. Drug Discov. 10: 945–963, https://doi.org/10.1038/nrd3599.Search in Google Scholar PubMed PubMed Central

Kalinska, M., Meyer-Hoffert, U., Kantyka, T., and Potempa, J. (2016). Kallikreins - the melting pot of activity and function. Biochimie 122: 270–282, https://doi.org/10.1016/j.biochi.2015.09.023.Search in Google Scholar PubMed PubMed Central

Kempaiah, P. and Kisiel, W. (2008). Human tissue factor pathway inhibitor-2 induces caspase-mediated apoptosis in a human fibrosarcoma cell line. Apoptosis 13: 702–715, https://doi.org/10.1007/s10495-008-0207-8.Search in Google Scholar PubMed

Kim, H., Son, S., and Shin, I. (2018). Role of the CCN protein family in cancer. BMB Rep 51: 486–492, https://doi.org/10.5483/bmbrep.2018.51.10.192.Search in Google Scholar

Konduri, S.D., Tasiou, A., Chandrasekar, N., Nicolson, G.L., and Rao, J.S. (2000). Role of tissue factor pathway inhibitor-2 (TFPI-2). in amelanotic melanoma (C-32). invasion. Clin. Exp. Metastasis 18: 303–308, https://doi.org/10.1023/a:1011085820250.10.1023/A:1011085820250Search in Google Scholar

Konduri, S.D., Tasiou, A., Chandrasekar, N., and Rao, J.S. (2001). Overexpression of tissue factor pathway inhibitor-2 (TFPI-2)., decreases the invasiveness of prostate cancer cells in vitro. Int. J. Oncol. 18: 127–131.10.3892/ijo.18.1.127Search in Google Scholar

Kong, D., Ma, D., Bai, H., Guo, H., Cai, X., Mo, W., Tang, Q., and Song, H. (2004). Expression and characterization of the first kunitz domain of human tissue factor pathway inhibitor-2. Biochem. Biophys. Res. Commun. 324: 1179–1185, https://doi.org/10.1016/j.bbrc.2004.09.179.Search in Google Scholar PubMed

Kryza, T., Achard, C., Parent, C., Marchand-Adam, S., Guillon-Munos, A., Iochmann, S., Korkmaz, B., Respaud, R., Courty, Y., and Heuzé-Vourc h, N. (2014). Angiogenesis stimulated by human kallikrein-related peptidase 12 acting via a platelet-derived growth factor B-dependent paracrine pathway. FASEB J. 28: 740–751, https://doi.org/10.1096/fj.13-237503.Search in Google Scholar PubMed

Kryza, T., Parent, C., Pardessus, J., Petit, A., Burlaud-Gaillard, J., Reverdiau, P., Iochmann, S., Labas, V., Courty, Y., and Heuzé-Vourch, N. (2018). Human kallikrein-related peptidase 12 stimulates endothelial cell migration by remodeling the fibronectin matrix. Sci. Rep. 8: 6331, https://doi.org/10.1038/s41598-018-24576-9.Search in Google Scholar PubMed PubMed Central

Kryza, T., Silva, M.L., Loessner, D., Heuzé-Vourc h, N., and Clements, J.A. (2016). The kallikrein-related peptidase family: dysregulation and functions during cancer progression. Biochimie 122: 283–299, https://doi.org/10.1016/j.biochi.2015.09.002.Search in Google Scholar PubMed

Lavergne, M., Jourdan, M.L., Blechet, C., Guyetant, S., Pape, A.L., Heuze-Vourch, N., Courty, Y., Lerondel, S., Sobilo, J., Iochmann, S., et al.. (2013). Beneficial role of overexpression of TFPI-2 on tumour progression in human small cell lung cancer. FEBS Open Bio 3: 291–301, https://doi.org/10.1016/j.fob.2013.06.004.Search in Google Scholar PubMed PubMed Central

Lenga Ma Bonda, W., Iochmann, S., Magnen, M., Courty, Y., and Reverdiau, P. (2018). Kallikrein-related peptidases in lung diseases. Biol. Chem. 399: 959–971, https://doi.org/10.1515/hsz-2018-0114.Search in Google Scholar PubMed

Li, X.S. and He, X.L. (2016). Kallikrein 12 downregulation reduces AGS gastric cancer cell proliferation and migration. Genet. Mol. Res. 15, https://doi.org/10.4238/gmr.15038452.Search in Google Scholar PubMed

Luo, L.Y. and Jiang, W. (2006). Inhibition profiles of human tissue kallikreins by serine protease inhibitors. Biol. Chem. 387: 813–816, https://doi.org/10.1515/bc.2006.103.Search in Google Scholar

Magnen, M., Gueugnon, F., Guillon, A., Baranek, T., Thibault, V.C., Petit-Courty, A., de Veer, S.J., Harris, J., Humbles, A.A., Si-Tahar, M., et al.. (2017). Kallikrein-related peptidase 5 contributes to H3N2 Influenza virus infection in human lungs. J. Virol. 91, https://doi.org/10.1128/jvi.00421-17.Search in Google Scholar PubMed PubMed Central

Memari, N., Diamandis, E.P., Earle, T., Campbell, A., Van Dekken, H., and Van der Kwast, T.H. (2007). Human kallikrein-related peptidase 12: antibody generation and immunohistochemical localization in prostatic tissues. Prostate 67: 1465–1474, https://doi.org/10.1002/pros.20596.Search in Google Scholar PubMed

Menashi, S., Fridman, R., Desrivieres, S., Lu, H., Legrand, Y., and Soria, C. (1994). Regulation of 92-kDa gelatinase B activity in the extracellular matrix by tissue kallikrein. Ann. N. Y. Acad. Sci. 732: 466–468, https://doi.org/10.1111/j.1749-6632.1994.tb24787.x.Search in Google Scholar PubMed

Meyer-Hoffert, U., Wu, Z., Kantyka, T., Fischer, J., Latendorf, T., Hansmann, B., Bartels, J., He, Y., Gläser, R., and Schröder, J.M. (2010). Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases. J. Biol. Chem. 285: 32174–32181, https://doi.org/10.1074/jbc.m109.091850.Search in Google Scholar PubMed PubMed Central

Michael, I.P., Sotiropoulou, G., Pampalakis, G., Magklara, A., Ghosh, M., Wasney, G., and Diamandis, E.P. (2005). Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression. J. Biol. Chem. 280: 14628–14635, https://doi.org/10.1074/jbc.m408132200.Search in Google Scholar PubMed

Mukai, S., Fukushima, T., Naka, D., Tanaka, H., Osada, Y., and Kataoka, H. (2008). Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases. FEBS J. 275: 1003–1017. https://doi.org/10.1111/j.1742-4658.2008.06265.x.Search in Google Scholar PubMed

Nagase, H., Enghild, J.J., Suzuki, K., and Salvesen, G. (1990). Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl).mercuric acetate. Biochemistry 29: 5783–5789, https://doi.org/10.1021/bi00476a020.Search in Google Scholar PubMed

Noël, A., Jost, M., and Maquoi, E. (2008). Matrix metalloproteinases at cancer tumor-host interface. Semin. Cell Dev. Biol. 19: 52–60, https://doi.org/10.1016/j.semcdb.2007.05.011.Search in Google Scholar PubMed

Petersen, L.C., Sprecher, C.A., Foster, D.C., Blumberg, H., Hamamoto, T., and Kisiel, W. (1996). Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. Biochemistry 35: 266–272, https://doi.org/10.1021/bi951501d.Search in Google Scholar PubMed

Prassas, I., Eissa, A., Poda, G., and Diamandis, E.P. (2015). Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat. Rev. Drug Discov. 14: 183–202, https://doi.org/10.1038/nrd4534.Search in Google Scholar PubMed

Qin, Y., Zhang, S., Gong, W., Li, J., Jia, J., and Quan, Z. (2012). Adenovirus-mediated gene transfer of tissue factor pathway inhibitor-2 inhibits gallbladder carcinoma growth in vitro and in vivo. Cancer Sci. 103: 723–730, https://doi.org/10.1111/j.1349-7006.2012.02218.x.Search in Google Scholar PubMed PubMed Central

Ramani, V.C., Kaushal, G.P., and Haun, R.S. (2011). Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains. Biochim. Biophys. Acta 1813: 1525–1531, https://doi.org/10.1016/j.bbamcr.2011.05.007.Search in Google Scholar PubMed PubMed Central

Ran, Y., Pan, J., Hu, H., Zhou, Z., Sun, L., Peng, L., Yu, L., Liu, J., and Yang, Z. (2009). A novel role for tissue factor pathway inhibitor-2 in the therapy of human esophageal carcinoma. Hum. Gene Ther. 20: 41–49, https://doi.org/10.1089/hum.2008.129.Search in Google Scholar PubMed

Rao, C.N., Mohanam, S., Puppala, A., and Rao, J.S. (1999). Regulation of ProMMP-1 and ProMMP-3 activation by tissue factor pathway inhibitor-2/matrix-associated serine protease inhibitor. Biochem. Biophys. Res. Commun. 255: 94–98, https://doi.org/10.1006/bbrc.1999.0153.Search in Google Scholar PubMed

Rao, C.N., Reddy, P., Liu, Y., O Toole, E., Reeder, D., Foster, D.C., Kisiel, W., and Woodley, D.T. (1996). Extracellular matrix-associated serine protease inhibitors (Mr 33,000, 31,000, and 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2. Arch. Biochem. Biophys. 335: 82–92, https://doi.org/10.1006/abbi.1996.0484.Search in Google Scholar PubMed

Rollin, J., Iochmann, S., Bléchet, C., Hubé, F., Régina, S., Guyétant, S., Lemarié, E., Reverdiau, P., and Gruel, Y. (2005). Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer. Br. J. Cancer 92: 775–783, https://doi.org/10.1038/sj.bjc.6602298.Search in Google Scholar PubMed PubMed Central

Schmidt, A.E., Chand, H.S., Cascio, D., Kisiel, W., and Bajaj, S.P. (2005). Crystal structure of Kunitz domain 1 (KD1) of tissue factor pathway inhibitor-2 in complex with trypsin. Implications for KD1 specificity of inhibition. J. Biol. Chem. 280: 27832–27838, https://doi.org/10.1074/jbc.m504105200.Search in Google Scholar

Stamenkovic, I. (2003). Extracellular matrix remodelling: the role of matrix metalloproteinases. J. Pathol. 200: 448–464, https://doi.org/10.1002/path.1400.Search in Google Scholar PubMed

Swarts, D.R., Van Neste, L., Henfling, M.E., Eijkenboom, I., Eijk, P.P., van Velthuysen, M.L., Vink, A., Volante, M., Ylstra, B., Van Criekinge, W., et al.. (2013). An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 34: 2726–2737, https://doi.org/10.1093/carcin/bgt271.Search in Google Scholar PubMed

Tang, Z., Geng, G., Huang, Q., Xu, G., Hu, H., Chen, J., and Li, J. (2010). Prognostic significance of tissue factor pathway inhibitor-2 in pancreatic carcinoma and its effect on tumor invasion and metastasis. Med. Oncol. 27: 867–875, https://doi.org/10.1007/s12032-009-9298-5.Search in Google Scholar PubMed

Wang, G., Huang, W., Li, W., Chen, S., Chen, W., Zhou, Y., Peng, P., and Gu, W. (2018). TFPI-2 suppresses breast cancer cell proliferation and invasion through regulation of ERK signaling and interaction with actinin-4 and myosin-9. Sci. Rep. 8: 14402, https://doi.org/10.1038/s41598-018-32698-3.Search in Google Scholar PubMed PubMed Central

Wu, D., Xiong, L., Wu, S., Jiang, M., Lian, G., and Wang, M. (2012). TFPI-2 methylation predicts poor prognosis in non-small cell lung cancer. Lung Cancer 76: 106–111, https://doi.org/10.1016/j.lungcan.2011.09.005.Search in Google Scholar PubMed

Xu, C., Wang, H., He, H., Zheng, F., Chen, Y., Zhang, J., Lin, X., Ma, D., and Zhang, H. (2013). Low expression of TFPI-2 associated with poor survival outcome in patients with breast cancer. BMC Cancer 13: 118, https://doi.org/10.1186/1471-2407-13-118.Search in Google Scholar PubMed PubMed Central

Xu, Y., Qin, X., Zhou, J., Tu, Z., Bi, X., Li, W., Fan, X., and Zhang, Y. (2011). Tissue factor pathway inhibitor-2 inhibits the growth and invasion of hepatocellular carcinoma cells and is inactivated in human hepatocellular carcinoma. Oncol. Lett. 2: 779–783, https://doi.org/10.3892/ol.2011.340.Search in Google Scholar PubMed PubMed Central

Yanamandra, N., Kondraganti, S., Gondi, C.S., Gujrati, M., Olivero, W.C., Dinh, D.H., and Rao, J.S. (2005). Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int. J. Cancer 115: 998–1005, https://doi.org/10.1002/ijc.20965.Search in Google Scholar PubMed

Yoon, H., Blaber, S.I., Evans, D.M., Trim, J., Juliano, M.A., Scarisbrick, I.A., and Blaber, M. (2008). Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis. Protein Sci. 17: 1998–2007, https://doi.org/10.1110/ps.036715.108.Search in Google Scholar PubMed PubMed Central

Yoon, H., Blaber, S.I., Li, W., Scarisbrick, I.A., and Blaber, M. (2013). Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases. Biol. Chem. 394: 137–147, https://doi.org/10.1515/hsz-2012-0249.Search in Google Scholar PubMed PubMed Central

Yousef, G.M. and Diamandis, E.P. (1999). The new kallikrein-like gene, KLK-L2. Molecular characterization, mapping, tissue expression, and hormonal regulation. J. Biol. Chem. 274: 37511–37516, https://doi.org/10.1074/jbc.274.53.37511.Search in Google Scholar PubMed

Yousef, G.M., Magklara, A., and Diamandis, E.P. (2000). KLK12 is a novel serine protease and a new member of the human kallikrein gene family-differential expression in breast cancer. Genomics 69: 331–341, https://doi.org/10.1006/geno.2000.6346.Search in Google Scholar PubMed

Zhao, E.H., Shen, Z.Y., Liu, H., Jin, X., and Cao, H. (2012). Clinical significance of human kallikrein 12 gene expression in gastric cancer. World J. Gastroenterol. 18: 6597–6604, https://doi.org/10.3748/wjg.v18.i45.6597.Search in Google Scholar PubMed PubMed Central

Received: 2020-12-18
Accepted: 2021-04-30
Published Online: 2021-05-12
Published in Print: 2021-09-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Biophysical applications in structural and molecular biology
  4. Research Articles/Short Communications
  5. Genes and Nucleic Acids
  6. Historic nucleic acids isolated by Friedrich Miescher contain RNA besides DNA
  7. Protein Structure and Function
  8. The extracellular region of bovine milk butyrophilin exhibits closer structural similarity to human myelin oligodendrocyte glycoprotein than to immunological BTN family receptors
  9. Structural insights into the repair mechanism of AGT for methyl-induced DNA damage
  10. Cell Biology and Signaling
  11. In vitro osteogenic activities of sulfated derivative of polysaccharide extracted from Tamarindus indica L.
  12. Synthesis and biological characterization of a new fluorescent probe for vesicular trafficking based on polyazamacrocycle derivative
  13. Properties of transmembrane helix TM1 of the DcuS sensor kinase of Escherichia coli, the stator for TM2 piston signaling
  14. Lefty A is involved in sunitinib resistance of renal cell carcinoma cells via regulation of IL-8
  15. Proteolysis
  16. Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor
https://doi.org/10.1515/hsz-2020-0389
Keywords for this article
CCN; extracellular matrix; lung cancer; matrix metalloproteinase; protease inhibitor; serine protease

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Biophysical applications in structural and molecular biology
  4. Research Articles/Short Communications
  5. Genes and Nucleic Acids
  6. Historic nucleic acids isolated by Friedrich Miescher contain RNA besides DNA
  7. Protein Structure and Function
  8. The extracellular region of bovine milk butyrophilin exhibits closer structural similarity to human myelin oligodendrocyte glycoprotein than to immunological BTN family receptors
  9. Structural insights into the repair mechanism of AGT for methyl-induced DNA damage
  10. Cell Biology and Signaling
  11. In vitro osteogenic activities of sulfated derivative of polysaccharide extracted from Tamarindus indica L.
  12. Synthesis and biological characterization of a new fluorescent probe for vesicular trafficking based on polyazamacrocycle derivative
  13. Properties of transmembrane helix TM1 of the DcuS sensor kinase of Escherichia coli, the stator for TM2 piston signaling
  14. Lefty A is involved in sunitinib resistance of renal cell carcinoma cells via regulation of IL-8
  15. Proteolysis
  16. Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 29.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2020-0389/html
Scroll to top button