Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers

Steven A. Stacker, Kaye Stenvers, Carol Caesar, Angela Vitali, Teresa Domagala, Edouard Nice, Sally Roufail, Richard J. Simpson, Robert Moritz, Terhi Karpanen, Kari Alitalo, Marc G. Achen

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Vascular endothelial growth factor-D (VEGF-D) binds and activates the endothelial cell tyrosine kinase receptors VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3), is mitogenic for endothelial cells, and shares structural homology and receptor specificity with VEGF-C. The primary translation product of VEGF-D has long N- and C-terminal polypeptide extensions in addition to a central VEGF homology domain (VHD). The VHD of VEGF-D is sufficient to bind and activate VEGFR-2 and VEGFR-3. Here we report that VEGF-D is proteolytically processed to release the VHD. Studies in 293EBNA cells demonstrated that VEGF-D undergoes N- and C-terminal cleavage events to produce numerous secreted polypeptides including a fully processed form of M(r) ~21,000 consisting only of the VHD, which is predominantly a non-covalent dimer. Biosensor analysis demonstrated that the VHD has ~290- and ~40-fold greater affinity for VEGFR-2 and VEGFR-3, respectively, compared with unprocessed VEGF-D. In situ hybridization demonstrated that embryonic lung is a major site of expression of the VEGF-D gene. Processed forms of VEGF-D were detected in embryonic lung indicating that VEGF-D is proteolytically processed in vivo.

Original languageEnglish
Pages (from-to)32127-32136
Number of pages10
JournalThe Journal of Biological Chemistry
Issue number45
Publication statusPublished - 5 Nov 1999
Externally publishedYes

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