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- Title
Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.
- Authors
McColl, Bradley K.; Paavonen, Karri; Karnezis, Tara; Harris, Nicole C.; Davydova, Natalia; Rothacker, Julie; Nice, Edourd C.; Harder, Kenneth W.; Roufail, Sally; Hibbs, Margaret L.; Rogers, Peter A. W.; Alitalo, Kari; Stacker, Steven A.; Achen, Marc G.
- Abstract
Vascular endothelial growth factor (VEGF)-D is a secreted glycoprotein that induces anglogenesis and lymphangiogenesis. It consists of a central domain, containing binding sites for VEGF receptor-2 (VEGFR-2) and VEGFR-3, and N- and C-terminal propeptides. It is secreted from the cell as homodimers of the full-length form that can be proteolytically processed to remove the propeptides. It was recently shown, using adenoviral gene delivery, that fully processed VEGF-D induces angiogenesis in vivo, whereas full-length VEGF-D does not. To better understand these observations, we monitored the effect of VEGF-D processing on receptor binding using a full-length VEGF-D mutant that cannot be processed. This mutant binds VEGFR-2, the receptor signaling for angiogenesis, with ∼17,000-fold lower affinity than mature VEGF-D, indicating the importance of processing for interaction with this receptor. Further, we show that members of the proprotein convertase (PC) family of proteases promote VEGF-D processing, which facilitates the VEGF-D/VEGFR-2 interaction. The PCs furin and PC5 promote cleavage of both propeptides, whereas PC7 promotes cleavage of the C-terminal propeptide only. The finding that PCs promote activation of VEGF-D and other proteins with roles in cancer such as matrix metalloproteinases, emphasizes the importance of these enzymes as potential regulators of tumor progress. ion and metastasis.
- Subjects
VASCULAR endothelial growth factors; GLYCOPROTEINS; PEPTIDES; NEOVASCULARIZATION; ENZYMES
- Publication
FASEB Journal, 2007, Vol 21, Issue 4, p1088
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-7060com