The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis
Geraldine Siegfried, … , Nabil G. Seidah, Abdel-Majid Khatib
Geraldine Siegfried, … , Nabil G. Seidah, Abdel-Majid Khatib
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1723-1732. https://doi.org/10.1172/JCI17220.
View: Text | PDF
Article Oncology

The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis

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 HSIIRR227SL 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 (220Q-VHSIIRR↓SLP230). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-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 (HSIIRR227SL to HSIISS227SL) 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.

Authors

Geraldine Siegfried, Ajoy Basak, James A. Cromlish, Suzanne Benjannet, Jadwiga Marcinkiewicz, Michel Chrétien, Nabil G. Seidah, Abdel-Majid Khatib

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
(a) Kinetic parameters Vmax(apparent) and Km(apparent) for the cleavage ...
(a) Kinetic parameters Vmax(apparent) and Km(apparent) for the cleavage of QVEGF-C by furin, PC5, and PC7. Various concentrations of QVEGF-C (0.5–200 μM) were incubated in the presence of furin, PC5, or PC7, and the fluorescence released at various times was measured at λex 320 nm and λem 420. (b) The data collected after either 1 hour or 4 hours of incubation were used to calculate Vmax(apparent) and Km(apparent) using GraFit software as described in Methods. The amounts of furin, PC5, and PC7 used in this study were adjusted to show similar levels of enzymatic activity when measured in the presence of the universal PC substrate, the fluorogenic peptide pERTKR-MCA (100 μM). RFU, raw fluorescence unit; app, apparent.