Heterodimerisation between VEGFR-1 and VEGFR-2 and not the homodimers of VEGFR-1 inhibit VEGFR-2 activity

Abstract Vascular endothelial growth factor (VEGF) signaling is tightly regulated by specific VEGF receptors (VEGF-R). Recently, we identified heterodimerisation between VEGFR-1 and VEGFR-2 (VEGFR1–2 ) to regulate VEGFR-2 function. However, both the mechanism of action and the relationship with VEGF...

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Bibliographic Details
Published in:Vascular pharmacology 2017-01, Vol.88, p.11-20
Main Authors: Cai, Meng, Wang, Keqing, Murdoch, Colin E, Gu, Yuchun, Ahmed, Asif
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Angiogenesis
Animals
Capillary tubes
Cardiovascular
Endothelial cells
Endothelial Cells - metabolism
Enzymes
Growth factors
Heterodimers
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Inhibition
Neovascularization, Physiologic - physiology
Oncology
Phosphatidylinositol 3-kinase (PI3K)
Phosphatidylinositol 3-Kinase - metabolism
Phosphorylation
Protein Multimerization
Receptors
Signal Transduction
Signaling
Stimulation
Swine
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF)
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-1 - metabolism
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vascular endothelial growth factor receptors
VEGF receptors
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Summary:Abstract Vascular endothelial growth factor (VEGF) signaling is tightly regulated by specific VEGF receptors (VEGF-R). Recently, we identified heterodimerisation between VEGFR-1 and VEGFR-2 (VEGFR1–2 ) to regulate VEGFR-2 function. However, both the mechanism of action and the relationship with VEGFR-1 homodimers remain unknown. The current study shows that activation of VEGFR1–2 , but not VEGFR-1 homodimers, inhibits VEGFR-2 receptor phosphorylation under VEGF stimulation in human endothelial cells. Furthermore, inhibition of phosphatidylinositol 3-kinase (PI3K) increases VEGFR-2 phosphorylation under VEGF stimulation. More importantly, inhibition of PI3K pathway abolishes the VEGFR1–2 mediated inhibition of VEGFR-2 phosphorylation. We further demonstrate that inhibition of PI3K pathway promotes capillary tube formation. Finally, the inhibition of PI3K abrogates the inhibition of in vitro angiogenesis mediated by VEGFR1–2 heterodimers. These findings demonstrate that VEGFR1–2 heterodimers and not VEGFR-1 homodimers inhibit VEGF-VEGFR-2 signaling by suppressing VEGFR-2 phosphorylation via PI3K pathway.
ISSN:1537-1891
1879-3649
DOI:10.1016/j.vph.2016.11.007