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J Biol Chem ; 286(29): 25947-62, 2011 Jul 22.
Article in English | MEDLINE | ID: mdl-21596751

ABSTRACT

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 α2ß1 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 α2ß1 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 α2ß1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express α2ß1 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.


Subject(s)
Angiostatic Proteins/metabolism , Heparan Sulfate Proteoglycans/metabolism , Integrin alpha2beta1/antagonists & inhibitors , Integrin alpha2beta1/metabolism , Peptide Fragments/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Angiostatic Proteins/chemistry , Angiostatic Proteins/pharmacology , Animals , Cell Line , Down-Regulation/drug effects , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Heparan Sulfate Proteoglycans/chemistry , Heparan Sulfate Proteoglycans/pharmacology , Humans , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Protein Binding , Protein Structure, Tertiary , Protein Transport , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Rats , Transcription, Genetic/drug effects , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-1/chemistry , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/chemistry
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