Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.

Abstract

Vascular endothelial growth factor (VEGF)-D is a secreted glycoprotein that induces angiogenesis 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 approximately 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 progression and metastasis.

• Authors: Bradley K McColl, Karri Paavonen, Tara Karnezis, Nicole C Harris, Natalia Davydova, Julie Rothacker, Edouard C Nice, Kenneth W Harder, Sally Roufail, Margaret L Hibbs, Peter A W Rogers, Kari Alitalo, Steven A Stacker, Marc G Achen
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 4 Pg. 1088-98 (Apr 2007) ISSN: 1530-6860 [Electronic] United States
• PMID: 17242158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbamates
• Glycoproteins
• Oligopeptides
• Vascular Endothelial Growth Factor D
• tetrapeptide carbamate
• Vascular Endothelial Growth Factor Receptor-2
• PCSK7 protein, human
• Pcsk7 protein, mouse
• Subtilisins

Topics

• Animals
• Carbamates (metabolism)
• Glycoproteins (metabolism)
• HeLa Cells
• Humans
• Lymphatic System (pathology)
• Mice
• Mice, Inbred BALB C
• Mutation
• Neovascularization, Pathologic
• Oligopeptides (metabolism)
• Protein Binding
• Subtilisins (metabolism)
• Vascular Endothelial Growth Factor D (chemistry, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)