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Kallikrein-Related Peptidase 14 Activates Zymogens of Membrane Type Matrix Metalloproteinases (MT-MMPs)—A CleavEx Based Analysis

1
Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
2
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
3
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
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Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland
5
Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759 Bremen, Germany
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Centre for Blood Research, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
8
School of Dentistry, University of Louisville, Louisville, KY 40202, USA
9
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4383; https://doi.org/10.3390/ijms21124383
Received: 14 May 2020 / Revised: 9 June 2020 / Accepted: 17 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue Biocatalysis: Mechanisms of Proteolytic Enzymes)
Kallikrein-related peptidases (KLKs) and matrix metalloproteinases (MMPs) are secretory proteinases known to proteolytically process components of the extracellular matrix, modulating the pericellular environment in physiology and in pathologies. The interconnection between these families remains elusive. To assess the cross-activation of these families, we developed a peptide, fusion protein-based exposition system (Cleavage of exposed amino acid sequences, CleavEx) aiming at investigating the potential of KLK14 to recognize and hydrolyze proMMP sequences. Initial assessment identified ten MMP activation domain sequences which were validated by Edman degradation. The analysis revealed that membrane-type MMPs (MT-MMPs) are targeted by KLK14 for activation. Correspondingly, proMMP14-17 were investigated in vitro and found to be effectively processed by KLK14. Again, the expected neo-N-termini of the activated MT-MMPs was confirmed by Edman degradation. The effectiveness of proMMP activation was analyzed by gelatin zymography, confirming the release of fully active, mature MT-MMPs upon KLK14 treatment. Lastly, MMP14 was shown to be processed on the cell surface by KLK14 using murine fibroblasts overexpressing human MMP14. Herein, we propose KLK14-mediated selective activation of cell-membrane located MT-MMPs as an additional layer of their regulation. As both, KLKs and MT-MMPs, are implicated in cancer, their cross-activation may constitute an important factor in tumor progression and metastasis. View Full-Text
Keywords: kallikrein 14; membrane-type MMP; CleavEx; fusion protein; zymogen activation kallikrein 14; membrane-type MMP; CleavEx; fusion protein; zymogen activation
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Falkowski, K.; Bielecka, E.; Thøgersen, I.B.; Bocheńska, O.; Płaza, K.; Kalińska, M.; Sąsiadek, L.; Magoch, M.; Pęcak, A.; Wiśniewska, M.; Gruba, N.; Wysocka, M.; Wojtysiak, A.; Brzezińska-Bodal, M.; Sychowska, K.; Pejkovska, A.; Rehders, M.; Butler, G.; Overall, C.M.; Brix, K.; Dubin, G.; Lesner, A.; Kozik, A.; Enghild, J.J.; Potempa, J.; Kantyka, T. Kallikrein-Related Peptidase 14 Activates Zymogens of Membrane Type Matrix Metalloproteinases (MT-MMPs)—A CleavEx Based Analysis. Int. J. Mol. Sci. 2020, 21, 4383.

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