title: 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.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: McColl
authors.forename: Karri
authors.initials: K
authors.lastname: Paavonen
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Harris
authors.forename: Natalia
authors.initials: N
authors.lastname: Davydova
authors.forename: Julie
authors.initials: J
authors.lastname: Rothacker
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
authors.forename: Sally
authors.initials: S
authors.lastname: Roufail
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.forename: Peter A W
authors.initials: PA
authors.lastname: Rogers
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
mesh_terms: 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*
chemical_list: 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