KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
- University of Helsinki, Finland
- Max Planck Institute for Heart and Lung Research, Germany
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
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.
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).
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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KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
eLife 8:e44478.
https://doi.org/10.7554/eLife.44478
