eLife (May 2019)

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

  • Sawan Kumar Jha,
  • Khushbu Rauniyar,
  • Ewa Chronowska,
  • Kenny Mattonet,
  • Eunice Wairimu Maina,
  • Hannu Koistinen,
  • Ulf-Håkan Stenman,
  • Kari Alitalo,
  • Michael Jeltsch

DOI
https://doi.org/10.7554/eLife.44478
Journal volume & issue
Vol. 8

Abstract

Read online

Vascular 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.

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