TY - JOUR T1 - KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D JF - eLife Y1 - 2019 A1 - Jha, Sawan Kumar A1 - Rauniyar, Khushbu A1 - Chronowska, Ewa A1 - Mattonet, Kenny A1 - Maina, Eunice Wairimu A1 - Koistinen, Hannu A1 - Stenman, Ulf-HÃ¥kan A1 - Alitalo, Kari A1 - Jeltsch, Michael KW - cancer biology KW - Cathepsin D KW - kallikrein-related peptidases KW - KLK3/PSA KW - Lymphangiogenesis KW - mouse KW - VEGF-C KW - VEGF-D AB - 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. VL - 8 SN - 2050-084X UR - https://elifesciences.org/articles/44478 JO - eLife ER -