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

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
Article number44478
JournaleLife
Volume8
Number of pages30
ISSN2050-084X
DOIs
Publication statusPublished - 17 May 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 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

Cite this

@article{718751260a5f489ca898b367652f69b6,
title = "KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D",
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.",
keywords = "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",
author = "Jha, {Sawan Kumar} and Khusbu Rauniyar and Ewa Chronowska and Kenny Mattonet and Eunice Maina and Hannu Koistinen and Stenman, {Ulf H{\aa}kan} and Kari Alitalo and Michael Jeltsch",
year = "2019",
month = "5",
day = "17",
doi = "10.7554/eLife.44478",
language = "English",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "ELIFE SCIENCES PUBLICATIONS LTD",

}

KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D. / Jha, Sawan Kumar; Rauniyar, Khusbu; Chronowska, Ewa; Mattonet, Kenny; Maina, Eunice; Koistinen, Hannu; Stenman, Ulf Håkan; Alitalo, Kari; Jeltsch, Michael.

In: eLife, Vol. 8, 44478, 17.05.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D

AU - Jha, Sawan Kumar

AU - Rauniyar, Khusbu

AU - Chronowska, Ewa

AU - Mattonet, Kenny

AU - Maina, Eunice

AU - Koistinen, Hannu

AU - Stenman, Ulf Håkan

AU - Alitalo, Kari

AU - Jeltsch, Michael

PY - 2019/5/17

Y1 - 2019/5/17

N2 - 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.

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.

KW - 3111 Biomedicine

KW - vascular biology

KW - Reproductive Biology

KW - CANCER METASTASIS

KW - 1182 Biochemistry, cell and molecular biology

KW - VEGF-C

KW - VEGF-D

KW - Prostate-specific antigen

KW - Cathepsin D

KW - CCBE1

KW - 1184 Genetics, developmental biology, physiology

KW - angiogenesis

KW - lymphangiogenesis

U2 - 10.7554/eLife.44478

DO - 10.7554/eLife.44478

M3 - Article

VL - 8

JO - eLife

JF - eLife

SN - 2050-084X

M1 - 44478

ER -