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| The EMBO Journal
(1997) 16, 3898–3911, doi:10.1093/emboj/16.13.3898 |
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| Proteolytic processing regulates receptor specificity and activity of VEGF-C |
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| Vladimir Joukov1, Tarja Sorsa1, Vijay Kumar1, Michael Jeltsch1, Lena Claesson-Welsh2, Yihai Cao3, Olli Saksela4, Nisse Kalkkinen5 and Kari Alitalo1 |
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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 Received 5 February 1997; Revised 27 March 1997. |
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| Abstract |
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| 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. |
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| Keywords: angiogenesis, growth factor, proteolytic processing, VEGF, VEGF-C |
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