Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 29, Pages 25947-25962Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.243626
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Funding
- National Institutes of Health [RO1 CA39481, RO1 CA47282, RO1 CA120975]
- Mizutani Foundation for Glycoscience
- National Research Service [T32 AA07463]
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Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the alpha 2 beta 1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the alpha 2 beta 1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the alpha 2 beta 1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express alpha 2 beta 1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.
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