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  • The EMBO Journal (1997) 16, 3898 - 3911
  • doi:10.1093/emboj/16.13.3898

Proteolytic processing regulates receptor specificity and activity of VEGF-C

Vladimir Joukov1, Tarja Sorsa1, Vijay Kumar1, Michael Jeltsch1, Lena Claesson-Welsh2, Yihai Cao3, Olli Saksela4, Nisse Kalkkinen5 and Kari Alitalo1,1

  1. Molecular/Cancer Biology Laboratory, University of Helsinki, 00014 Helsinki, Finland
  2. Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden
  3. Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77, Stockholm, Sweden
  4. Department of Virology, Haartman Institute, PL21 (Haartmaninkatu 3), University of Helsinki, 00014 Helsinki, Finland
  5. Biotechnology Institute, PL52, University of Helsinki, 00014 Helsinki, Finland

Correspondence to:

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Received 5 February 1997; Revised 27 March 1997

The recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant 'mature' VEGF-C made in yeast bound VEGFR-3 (KD = 135 pM) and VEGFR-2 (KD = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure–function relationships in the PDGF/VEGF family.

  • Keywords:

    • angiogenesis,
    • growth factor,
    • proteolytic processing,
    • VEGF,
    • VEGF-C