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

eLife

  ^{1    1    2    2    3    4    4    5    6} 

[1] Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland;Helsinki University Hospital, Helsinki, Finland;Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland;Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland;Jagiellonian University Medical College, Cracow, Poland;Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland;Wihuri Research Institute, Helsinki, Finland;Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Wihuri Research Institute, Helsinki, Finland;Helsinki University Hospital, Helsinki, Finland;Translational Cancer Medicine Research Program, University of Helsinki, Helsinki, Finland;

关键词: VEGF-C;    VEGF-D;    KLK3/PSA;    Cathepsin D;    kallikrein-related peptidases;    lymphangiogenesis;    Mouse;   

DOI  :  10.7554/eLife.44478

来源: publisher

【 摘 要 】

10.7554/eLife.44478.001Vascular 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 VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.

【 授权许可】

CC BY