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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.08-107219v1 22/8/3078    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Cébe-Suarez, S. Articles by Ballmer-Hofer, K. PubMed PubMed Citation Articles by Cébe-Suarez, S. Articles by Ballmer-Hofer, K.

Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR

Stéphanie Cébe-Suarez^*,1,2, Felix S. Grünewald^,2, Rolf Jaussi, Xiujuan Li, Lena Claesson-Welsh, Dorothe Spillmann, Andrew A. Mercer^||, Andrea E. Prota and Kurt Ballmer-Hofer^*,3

^* Molecular Cell Biology and

Structural Biology, Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland;

Department of Genetics and Pathology, Rudbeck Laboratory, and

Department of Medical Biochemistry and Microbiology (IMBIM), The Biomedical Center, Uppsala University, Uppsala, Sweden; and

^|| Virus Research Unit, Department of Microbiology and Immunology, University of Otago, New Zealand

³Correspondence: Paul Scherrer Institut, Laboratory of Biomolecular Research, Molecular Cell Biology, Bldg. OFLC 102, 5232 Villigen-PSI Switzerland. E-mail: kurt.ballmer{at}psi.ch

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-A₁₆₅) 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.

Key Words: neuropilin • angiogenesis • heparin sulfate • pox virus • vascular endothelial growth factor

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				H. Kawamura, X. Li, K. Goishi, L. A. van Meeteren, L. Jakobsson, S. Cebe-Suarez, A. Shimizu, D. Edholm, K. Ballmer-Hofer, L. Kjellen, et al. Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization Blood, November 1, 2008; 112(9): 3638 - 3649. [Abstract] [Full Text] [PDF]