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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 397, Issue 12

Issues

In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B

Janet C. Reid
  • Mater Research Institute – University of Queensland, Woolloongabba, Queensland 4102, Australia
  • Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia
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/ Nigel C. Bennett
  • Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia
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/ Carson R. Stephens
  • Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia
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/ Melanie L. Carroll
  • Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia
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/ Viktor Magdolen
  • Klinische Forschergruppe der Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany
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/ Judith A. Clements
  • Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland 4102, Australia
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/ John D. Hooper
  • Corresponding author
  • Mater Research Institute – University of Queensland, Woolloongabba, Queensland 4102, Australia
  • Email
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Published Online: 2016-08-17 | DOI: https://doi.org/10.1515/hsz-2016-0163

Abstract

Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5–10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.

Keywords: hepatocyte growth factor; HGF inhibitor; kallikrein-related peptidase 14; Met; prostate cancer

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About the article

Received: 2016-04-01

Accepted: 2016-08-10

Published Online: 2016-08-17

Published in Print: 2016-12-01


Funding Source: National Health and Medical Research Council

Award identifier / Grant number: 614206

Funding Source: Cancer Council Queensland

Award identifier / Grant number: APP1021827

Funding Source: Prostate Cancer Foundation of Australia

Award identifier / Grant number: PG 3810

Funding Source: Australian Research Council

Award identifier / Grant number: FT120100917

We thank Dr. Yaowu He (University of Queensland) for technical advice, and Dr. Daniel Kirchhofer (Genentech) for the generous gift of recombinant hepsin, HAI-1A and HAI-1B. This work was supported by funding from the National Health and Medical Research Council of Australia (grant 614206), Cancer Council Queensland (grant APP1021827), Prostate Cancer Foundation of Australia (grant PG 3810) and Australian Research Council (Future Fellowship FT120100917) to J.D.H., a mobility grant (Personalized Medicine) from the German Academic Exchange Service (DAAD) to J.A.C., V.M., and J.D.H., a National Health and Medical Research Council of Australia Principal Research Fellowship to J.A.C., and an Australian Postgraduate Award, and Smart State PhD stipend and Queensland University of Technology top-up and write-up scholarships to J.C.R.


Citation Information: Biological Chemistry, Volume 397, Issue 12, Pages 1299–1305, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2016-0163.

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