Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.44478
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Funding
- Academy of Finland [265982, 307366, 272683, 273612, 273817]
- Finnish Foundation for Cardiovascular Research
- Jane ja Aatos Erkon Saatio
- Cancer Society of Finland
- Magnus Ehrnroothin Saatio
- K. Albin Johanssons Stiftelse
- University of Helsinki
- Sigrid Juselius Foundation
- Laboratoriolaaketieteen Edistamissaatio
- European Research Council Horizon 2020 Research and Innovation programme [743155]
- Wihuri Research Institute
- Novo Nordisk Foundation
- Biomedicum Helsinki-saatio
- Paivikki and Sakari Sohlberg Foundation
- Academy of Finland (AKA) [272683, 272683, 265982, 273612, 265982, 307366, 273612, 307366] Funding Source: Academy of Finland (AKA)
- European Research Council (ERC) [743155] Funding Source: European Research Council (ERC)
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Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, for example 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 VEGFC-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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