Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.
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.
McColl
Bradley K
BK
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia.
Paavonen
Karri
K
Karnezis
Tara
T
Harris
Nicole C
NC
Davydova
Natalia
N
Rothacker
Julie
J
Nice
Edouard C
EC
Harder
Kenneth W
KW
Roufail
Sally
S
Hibbs
Margaret L
ML
Rogers
Peter A W
PA
Alitalo
Kari
K
Stacker
Steven A
SA
Achen
Marc G
MG
D000818:Animals; D002219:Carbamates / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008208:Lymphatic System / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000378:metabolism*; D011485:Protein Binding; D013381:Subtilisins / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000737:chemistry / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D002219:Carbamates; D006023:Glycoproteins; D009842:Oligopeptides; D042643:Vascular Endothelial Growth Factor D; C075359:tetrapeptide carbamate; D040301:Vascular Endothelial Growth Factor Receptor-2; C099101:PCSK7 protein, human; C490930:Pcsk7 protein, mouse; D013381:Subtilisins