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Orf virus VEGF‐E NZ2 promotes paracellular NRP‐1/VEGFR‐2 coreceptor assembly via the peptide RPPR
Author(s) -
Cébe-Suarez Stéphanie,
Grünewald Felix S.,
Jaussi Rolf,
Li Xiujuan,
Claesson-Welsh Lena,
Spillmann Dorothe,
Mercer Andrew A.,
Prota Andrea E.,
Ballmer-Hofer Kurt
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-107219
Subject(s) - receptor tyrosine kinase , angiogenesis , chemistry , microbiology and biotechnology , receptor , phosphorylation , biology , tyrosine , s1pr1 , kinase insert domain receptor , tyrosine kinase , vascular endothelial growth factor , vascular endothelial growth factor a , biochemistry , vegf receptors , cancer research
Vascular endothelial growth factors (VEGFs) interact with the receptor tyrosine kinases (RTKs) VEGFR‐1, ‐2, and ‐3; neuropilins (NRPs); and heparan sulfate (HS) proteoglycans. VEGF RTKs signal to downstream targets upon ligand‐induced tyrosine phosphorylation, while NRPs and HS act as coreceptors that lack enzymatic activity yet modulate signal output by VEGF RTKs. VEGFs exist in various isoforms with distinct receptor specificity and biological activity. Here, a series of mammalian VEGF‐A splice variants and orf virus VEGF‐Es, as well as chimeric and mutant VEGF variants, were characterized to determine the motifs required for binding to NRP‐1 in the absence (VEGF‐E) or presence (VEGF‐A 165 ) of an HS‐binding sequence. We identified the carboxyterminal peptides RPPR and DKPRR as the NRP‐1 binding motifs of VEGF‐E and VEGF‐A, respectively. RPPR had significantly higher affinity for NRP‐1 than DKPRR. VEGFs containing an RPPR motif promoted HS‐independent coreceptor complex assembly between VEGFR‐2 and NRP‐1, independent of whether these receptors were expressed on the same or separate cells grown in cocultures. Functional studies showed that stable coreceptor assembly by VEGF correlated with its ability to promote vessel formation in an embryoid body angiogenesis assay.—Cébe‐Suarez, S., Grünewald, F. S., Jaussi, R., Li, X., Claesson‐Welsh, L., Spillmann, D., Mercer, A. A., Prota, A. E., Ballmer‐Hofer, K. Orf virus VEGF‐E NZ2 promotes paracellular NRP‐1/VEGFR‐2 coreceptor assembly via the peptide RPPR. FASEB J. 22, 3078–3086 (2008)