Sammanfattning

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.
Originalspråkengelska
Artikelnummere44478
TidskrifteLife
Volym8
ISSN2050-084X
DOI
StatusPublicerad - 17 maj 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3111 Biomedicinska vetenskaper
  • 1182 Biokemi, cell- och molekylärbiologi
  • 1184 Genetik, utvecklingsbiologi, fysiologi

Citera det här

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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 Michael Jeltsch and Khusbu Rauniyar and Ewa Chronowska and Eunice Maina and Hannu Koistinen and Stenman, {Ulf H{\aa}kan} and Kari Alitalo and Kenny Mattonet",
year = "2019",
month = "5",
day = "17",
doi = "10.7554/eLife.44478",
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volume = "8",
journal = "eLife",
issn = "2050-084X",
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KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D. / Jha, Sawan Kumar; Jeltsch, Michael; Rauniyar, Khusbu; Chronowska, Ewa; Maina, Eunice; Koistinen, Hannu; Stenman, Ulf Håkan; Alitalo, Kari; Mattonet, Kenny.

I: eLife, Vol. 8, e44478, 17.05.2019.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

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

AU - Jha, Sawan Kumar

AU - Jeltsch, Michael

AU - Rauniyar, Khusbu

AU - Chronowska, Ewa

AU - Maina, Eunice

AU - Koistinen, Hannu

AU - Stenman, Ulf Håkan

AU - Alitalo, Kari

AU - Mattonet, Kenny

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.

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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

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ER -