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

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Jha , S K , Rauniyar , K , Chronowska , E , Mattonet , K , Maina , E , Koistinen , H , Stenman , U H , Alitalo , K & Jeltsch , M 2019 , ' KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D ' , eLife , vol. 8 , 44478 . https://doi.org/10.7554/eLife.44478

Title: KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
Author: Jha, Sawan Kumar; Rauniyar, Khusbu; Chronowska, Ewa; Mattonet, Kenny; Maina, Eunice; Koistinen, Hannu; Stenman, Ulf Håkan; Alitalo, Kari; Jeltsch, Michael
Contributor: University of Helsinki, Michael Jeltsch / Principal Investigator
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, Department of Clinical Chemistry and Hematology
University of Helsinki, Department of Clinical Chemistry and Hematology
University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
Date: 2019-05-17
Number of pages: 30
Belongs to series: eLife
ISSN: 2050-084X
URI: http://hdl.handle.net/10138/304596
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.
Subject: 3111 Biomedicine
vascular biology
Reproductive Biology
CANCER METASTASIS
1182 Biochemistry, cell and molecular biology
VEGF-C
VEGF-D
Prostate-specific antigen
Cathepsin D
CCBE1
1184 Genetics, developmental biology, physiology
angiogenesis
lymphangiogenesis
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