title: Vascular endothelial growth factor modulates the Tie-2:Tie-1 receptor complex.
abstract: The receptor tyrosine kinase Tie-1 is expressed predominantly in endothelial cells where it physically associates with the related receptor Tie-2. Positive signalling through Tie-2 is associated with microvessel stability and suppression of this signal is thought to be required for vascular endothelial growth factor (VEGF)-induced microvessel remodelling or growth. Here we examine the effects of VEGF on Tie-1 and the Tie-2:Tie-1 complex. We show that VEGF induces generation of the Tie-1 endodomain and loss of the full-length receptor. The effects of VEGF on endodomain formation are not suppressed by inhibitors of protein kinase C and do not involve the nitric oxide signalling pathway. Tyrosine kinase inhibitors, in contrast, do abolish endodomain generation in response to the endothelial growth factor. VEGF stimulation of cells does not cause dissociation of the Tie-2:Tie-1 complex; rather the complex is converted to a form comprising the full-length-Tie-2 and Tie-1 endodomain. VEGF can therefore switch the Tie-2:Tie-1 complex between two different forms in endothelial cells. The ability of VEGF to modulate Tie-1 and the Tie-2:Tie-1 complex provides a mechanism whereby this initiator of vessel growth and remodelling can directly modulate receptors involved in vessel stabilization. Such cross-talk is likely to be important in the coordinate control of blood vessel formation during development and in postnatal angiogenesis.
authors.affiliation: Department of Surgery, University of Leicester, RKCSB, Leicester, LE2 7LX, United Kingdom.
authors.forename: Achilleas C
authors.initials: AC
authors.lastname: Tsiamis
authors.forename: Paul N
authors.initials: PN
authors.lastname: Morris
authors.forename: Marie B
authors.initials: MB
authors.lastname: Marron
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Brindle
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D042764:Receptors, TIE; D015398:Signal Transduction; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D004247:DNA; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D042764:Receptors, TIE