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

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  • Katherine Falkowski, Jagiellonian University in Kraków
  • ,
  • Ewa Bielecka, Jagiellonian University in Kraków
  • ,
  • Ida B. Thøgersen
  • Oliwia Bocheńska, Jagiellonian University in Kraków
  • ,
  • Karolina Płaza, Jagiellonian University in Kraków
  • ,
  • Magdalena Kalińska, Jagiellonian University in Kraków
  • ,
  • Laura Sąsiadek, Jagiellonian University in Kraków
  • ,
  • Małgorzata Magoch, Jagiellonian University in Kraków
  • ,
  • Aleksandra Pęcak, Jagiellonian University in Kraków
  • ,
  • Magdalena Wiśniewska, Jagiellonian University in Kraków
  • ,
  • Natalia Gruba, University of Gdansk
  • ,
  • Magdalena Wysocka, University of Gdansk
  • ,
  • Anna Wojtysiak, University of Gdansk
  • ,
  • Magdalena Brzezińska-Bodal, University of Gdansk
  • ,
  • Kamila Sychowska, University of Gdansk
  • ,
  • Anastasija Pejkovska, Jacobs University
  • ,
  • Maren Rehders, Jacobs University
  • ,
  • Georgina Butler, University of British Columbia
  • ,
  • Christopher M. Overall, University of British Columbia
  • ,
  • Klaudia Brix, Jacobs University
  • ,
  • Grzegorz Dubin, Jagiellonian University in Kraków
  • ,
  • Adam Lesner, University of Gdansk
  • ,
  • Andrzej Kozik, Jagiellonian University in Kraków
  • ,
  • Jan J. Enghild
  • Jan Potempa, Jagiellonian University in Kraków, University of Louisville
  • ,
  • Tomasz Kantyka, Jagiellonian University in Kraków, University of Bergen

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.

OriginalsprogEngelsk
Artikelnummer4383
TidsskriftInternational Journal of Molecular Sciences
Vol/bind21
Nummer12
ISSN1661-6596
DOI
StatusUdgivet - jun. 2020

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