Chimeric VEGFRs are activated by a small-molecule dimerizer and mediate downstream signalling cascades in endothelial cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2000-11-09

AUTHORS

Emma L Knight, Andrea J Warner, Anthony Maxwell, Sally A Prigent

ABSTRACT

Despite much interest in vascular endothelial growth factor (VEGF) and its receptors (VEGFRs -1 and -2), VEGF-induced signalling cascades remain incompletely defined. Attempts to assign individual responses to a particular receptor have used either transfected cell lines, receptor-specific growth factors or antisense oligonucleotides. Such studies have attributed the majority of VEGF-induced responses to activation of VEGFR-2. As a consequence of poor growth factor-induced VEGFR-1 autophosphorylation however, observations from these studies may instead reflect the relative activation of the two receptors. We have generated novel chimeric VEGF receptors in which the dimerization domain of the B subunit of DNA gyrase is fused to the cytoplasmic domain of VEGFRs -1 and -2. When expressed in porcine aortic endothelial cells, both chimeric VEGFR-1 and -2 autophosphorylate in response to addition of the small-molecule dimerizing agent, coumermycin. Once activated, both receptors induce downstream signalling cascades, exemplified here by the activation of MAPK, PLCγ and PKB/Akt. Furthermore, we demonstrate that the Y1175 residue of VEGFR-2 is essential for the activation of PLCγ mediated by this chimeric receptor. In contrast to previous reports which show a limited ability of VEGFR-1 to mediate signalling cascades, we show that once sufficiently activated, VEGFR-1 signals in a similar manner to VEGFR-2 in endothelial cells. More... »

PAGES

5398-5405

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1203915

DOI

http://dx.doi.org/10.1038/sj.onc.1203915

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024913467

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/11103941


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