Abstract
The secreted glycoprotein vascular endothelial growth factor-D (VEGF-D) is angiogenic, lymphangiogenic, and promotes metastatic spread of tumor cells via lymphatic vessels. VEGF-D consists of a receptor-binding domain (VEGF homology domain) and N- and C-terminal propeptides. Proteolytic processing produces numerous forms of human VEGF-D, including fully processed derivatives (containing only the VEGF homology domain), partially processed, and unprocessed derivatives. Proteolysis is essential to generate human VEGF-D that binds the angiogenic receptor VEGF receptor-2 (VEGFR-2) and the lymphangiogenic receptor VEGFR-3 with high affinity. Here, we report that alternative use of an RNA splice donor site in exon 6 of the mouse VEGF-D gene produces two different protein isoforms, VEGF-D(358) and VEGF-D(326), with distinct C termini. The two isoforms were both expressed in all adult mouse tissues and embryonic stages of development analyzed. Both isoforms are proteolytically processed in a similar fashion to human VEGF-D to generate a range of secreted derivatives and bind and cross-link VEGFR-3 with similar potency. The isoforms are differently glycosylated when expressed in vitro. This study demonstrates that RNA splicing, protein glycosylation, and proteolysis are mechanisms for generating structural diversity of mouse VEGF-D.
Highlights
Members of the vascular endothelial growth factor (VEGF)1 family of secreted glycoproteins are important regulators of vascular development
This study demonstrates that RNA splicing, protein glycosylation, and proteolysis are mechanisms for generating structural diversity of mouse vascular endothelial growth factor-D (VEGF-D)
That consists of VEGF-C [8, 9] and VEGF-D [10] ( known as “c-Fos-induced growth factor” or FIGF [11]). These two growth factors are structurally and functionally related, because they are the only human VEGFs that bind both of the cell surface receptor tyrosine kinases VEGF receptor-2 (VEGFR-2) (KDR/Flk1) and VEGFR-3 (Flt4) [8, 10] that signal for angiogenesis and lymphangiogenesis, respectively [12,13,14]
Summary
Members of the vascular endothelial growth factor (VEGF)1 family of secreted glycoproteins are important regulators of vascular development (for review see Ref. 1). We report that alternative RNA splicing generates two different isoforms of mouse VEGF-D protein with distinct Cterminal propeptides.
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