Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers.
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) approximately 21,000 consisting only of the VHD, which is predominantly a non-covalent dimer. Biosensor analysis demonstrated that the VHD has approximately 290- and approximately 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.
Stacker
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Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. steven.stacker@ludwig.edu.au
Stenvers
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Caesar
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Vitali
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Domagala
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Nice
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Roufail
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Simpson
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Moritz
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Karpanen
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Alitalo
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Achen
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D002455:Cell Division; D002460:Cell Line; D019281:Dimerization; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007202:Indicators and Reagents; D009842:Oligopeptides; D010455:Peptides; D011499:Protein Processing, Post-Translational; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D011975:Receptors, Mitogen / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3
D016228:Endothelial Growth Factors; D007202:Indicators and Reagents; D009842:Oligopeptides; D010455:Peptides; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D042643:Vascular Endothelial Growth Factor D; C085706:FLAG peptide; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3