Vascular Endothelial Growth Factor Modulates the TIE-2:TIE-1 Receptor Complex

• Published in: Microvascular research Vol. 63; no. 2; pp. 149 - 158
• Main Authors: Tsiamis, Achilleas C., Morris, Paul N., Marron, Marie B., Brindle, Nicholas P.J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.03.2002; Elsevier
• Subjects: angiogenesis; Biological and medical sciences; Blood vessels and receptors; Blotting, Western; Cells, Cultured; DNA - metabolism; Dose-Response Relationship, Drug; endothelial; Endothelial Growth Factors - metabolism; Endothelium, Vascular - cytology; Fundamental and applied biological sciences. Psychology; Humans; Lymphokines - metabolism; Nitric Oxide - metabolism; Precipitin Tests; Protein Binding; Protein Structure, Tertiary; Protein-Tyrosine Kinases - metabolism; receptor; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, TIE-1; Receptor, TIE-2; Receptors, Cell Surface - metabolism; Receptors, TIE; Signal Transduction; Time Factors; tyrosine kinase; Umbilical Veins - cytology; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vertebrates: cardiovascular system; receptor; angiogenesis; endothelial; tyrosine kinase; Human; Angiogenesis; Endothelial cell; Vascular endothelium growth factor; Enzyme; Transferases; Blood vessel; Circulatory system; In vitro; Protein-tyrosine kinase; Umbilical vein; Biological receptor
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1006/mvre.2001.2377

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.