KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D

  1. Sawan Kumar Jha
  2. Khushbu Rauniyar
  3. Ewa Chronowska
  4. Kenny Mattonet
  5. Eunice Wairimu Maina
  6. Hannu Koistinen
  7. Ulf-Håkan Stenman
  8. Kari Alitalo
  9. Michael Jeltsch  Is a corresponding author
  1. University of Helsinki, Finland
  2. Max Planck Institute for Heart and Lung Research, Germany
  3. Wihuri Research Institute, Finland

Abstract

Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, e.g. in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Sawan Kumar Jha

    Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1898-4928
  2. Khushbu Rauniyar

    Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5485-7040
  3. Ewa Chronowska

    Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  4. Kenny Mattonet

    Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9705-8086
  5. Eunice Wairimu Maina

    Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Hannu Koistinen

    Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  7. Ulf-Håkan Stenman

    Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Kari Alitalo

    Wihuri Research Institute, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael Jeltsch

    Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
    For correspondence
    michael@jeltsch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2890-7790

Funding

Academy of Finland (265982)

  • Michael Jeltsch

European Research Council (Horizon 2020 Research and Innovation programme 743155)

  • Kari Alitalo

Wihuri Research Institute

  • Kari Alitalo

Academy of Finland Centre of Excellence Program 2014-2019 (307366)

  • Kari Alitalo

Novo Nordisk Foundation

  • Kari Alitalo

Cancer Society of Finland

  • Sawan Kumar Jha

Biomedicum Helsinki-säätiö

  • Sawan Kumar Jha

Päivikki and Sakari Sohlberg Foundation

  • Khushbu Rauniyar

Wihuri Research Institute

  • Sawan Kumar Jha

Academy of Finland (272683)

  • Michael Jeltsch

Academy of Finland (273612)

  • Michael Jeltsch

Finnish Foundation for Cardiovascular Research

  • Michael Jeltsch

Academy of Finland (273817)

  • Michael Jeltsch

Jane ja Aatos Erkon Säätiö

  • Michael Jeltsch

Cancer Society of Finland

  • Michael Jeltsch

Magnus Ehrnroothin Säätiö

  • Michael Jeltsch

K Albin Johansson Foundation

  • Michael Jeltsch

Integrated Life Science Doctoral Program

  • Sawan Kumar Jha

Sigrid Jusélius Foundation

  • Hannu Koistinen

Laboratoriolääketieteen edistämissäätiö

  • Hannu Koistinen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of

Ethics

Animal experimentation: All animal experiments carried out in this study were performed according to guidelines and regulations approved by the National Board for Animal Experiments of the Provincial State Office of Southern Finland (ESAVI/7012/04.10.07/2016).

Version history

  1. Received: January 2, 2019
  2. Accepted: May 16, 2019
  3. Accepted Manuscript published: May 17, 2019 (version 1)
  4. Version of Record published: June 21, 2019 (version 2)

Copyright

© 2019, Jha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sawan Kumar Jha
  2. Khushbu Rauniyar
  3. Ewa Chronowska
  4. Kenny Mattonet
  5. Eunice Wairimu Maina
  6. Hannu Koistinen
  7. Ulf-Håkan Stenman
  8. Kari Alitalo
  9. Michael Jeltsch
(2019)
KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
eLife 8:e44478.
https://doi.org/10.7554/eLife.44478

Share this article

https://doi.org/10.7554/eLife.44478

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