Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1.
Vascular endothelial growth factor B (VEGF-B) is expressed in various tissues, especially strongly in the heart, and binds selectively to one of the VEGF receptors, VEGFR-1. The two splice isoforms, VEGF-B(167) and VEGF-B(186), have identical NH(2)-terminal cystine knot growth factor domains but differ in their COOH-terminal domains which give these forms their distinct biochemical properties. In this study, we show that both splice isoforms of VEGF-B bind specifically to Neuropilin-1 (NRP1), a receptor for collapsins/semaphorins and for the VEGF(165) isoform. The NRP1 binding of VEGF-B could be competed by an excess of VEGF(165). The binding of VEGF-B(167) was mediated by the heparin binding domain, whereas the binding of VEGF-B(186) to NRP1 was regulated by exposure of a short COOH-terminal proline-rich peptide upon its proteolytic processing. In immunohistochemistry, NRP1 distribution was found to be overlapping or adjacent to known sites of VEGF-B expression in several tissues, in particular in the developing heart, suggesting the involvement of VEGF-B in NRP1-mediated signaling.
Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland.
T
T
Makinen
B
B
Olofsson
T
T
Karpanen
U
U
Hellman
S
S
Soker
M
M
Klagsbrun
U
U
Eriksson
K
K
Alitalo
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039942:Neuropilin-1; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D042561:Vascular Endothelial Growth Factor B
D016228:Endothelial Growth Factors; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B; D039942:Neuropilin-1