UBC Faculty Research and Publications

Kallikrein-Related Peptidase 14 Activates Zymogens of Membrane Type Matrix Metalloproteinases (MT-MMPs)—A CleavEx Based Analysis Falkowski, Katherine; Bielecka, Ewa; Thøgersen, Ida B.; Bocheńska, Oliwia; Płaza, Karolina; Kalińska, Magdalena; Sąsiadek, Laura; Magoch, Małgorzata; Pęcak, Aleksandra; Wiśniewska, Magdalena; Gruba, Natalia; Wysocka, Magdalena; Wojtysiak, Anna; Brzezińska-Bodal, Magdalena; Sychowska, Kamila; Pejkovska, Anastasija; Rehders, Maren; Butler, Georgina; Overall, Christopher M; Brix, Klaudia; Dubin, Grzegorz; Lesner, Adam; Kozik, Andrzej; Enghild, Jan J.; Potempa, Jan; Kantyka, Tomasz

Abstract

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.

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