title: Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Post Office Box 2008, Victoria 3050, Australia.
authors.forename: M E
authors.initials: ME
authors.lastname: Baldwin
authors.forename: S
authors.initials: S
authors.lastname: Roufail
authors.forename: M M
authors.initials: MM
authors.lastname: Halford
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: S A
authors.initials: SA
authors.lastname: Stacker
authors.forename: M G
authors.initials: MG
authors.lastname: Achen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042643:Vascular Endothelial Growth Factor D
chemical_list: D016228:Endothelial Growth Factors; D020033:Protein Isoforms; D042643:Vascular Endothelial Growth Factor D