The Secretory Proprotein Convertases Furin, PC5, and PC7 Activate VEGF-C to Induce Tumorigenesis

J Clin Invest. 2003 Jun;111(11):1723-32. doi: 10.1172/JCI17220.

Abstract

The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR(227)SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C ((220)Q-VHSIIRR downward arrow SLP(230)). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of alpha2-macroglobulin and alpha1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR(227)SL to HSIISS(227)SL) inhibits angiogenesis and lymphangiogenesis as well as tumor growth. Our findings demonstrate the processing of proVEGF-C by PCs and highlight the potential use of PC inhibitors as agents for inhibiting malignancies induced by VEGF-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Blotting, Western
  • CHO Cells
  • Carbamates / metabolism*
  • Cell Transformation, Neoplastic*
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Endothelial Growth Factors / metabolism*
  • Furin
  • Humans
  • Immunohistochemistry
  • Kinetics
  • Mutation
  • Neoplasms / metabolism*
  • Oligopeptides / metabolism*
  • Peptide Biosynthesis
  • Precipitin Tests
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subtilisins / metabolism*
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor C

Substances

  • Carbamates
  • Endothelial Growth Factors
  • Oligopeptides
  • RNA, Messenger
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor C
  • tetrapeptide carbamate
  • PCSK7 protein, human
  • Pcsk7 protein, mouse
  • Subtilisins
  • Furin