Proteolytic processing regulates receptor specificity and activity of VEGF-C

EMBO J. 1997 Jul 1;16(13):3898-911. doi: 10.1093/emboj/16.13.3898.


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 (K[D] = 135 pM) and VEGFR-2 (K[D] = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies / metabolism
  • COS Cells
  • Dimerization
  • Disulfides
  • Endopeptidases / metabolism
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism*
  • Endothelium, Vascular / metabolism
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Rabbits
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Growth Factor / metabolism*
  • Receptors, Vascular Endothelial Growth Factor
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor C


  • Antibodies
  • Disulfides
  • Endothelial Growth Factors
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor C
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Endopeptidases

Associated data

  • GENBANK/X94216